Lymphoid Cells: B, T, and NK Cells

Lymphoid Lineage Cells

• Lymphocytes differentiate along lymphocytic pathways.
• B lymphocytes, or B cells, reside in the bone marrow and synthesize immunoglobulin molecules; only B cells/plasma cells can do this.
• Some lymphoid cells migrate from bone marrow to the thymus, where they differentiate into thymus-derived lymphocytes, also known as T cells.
• Natural killer (NK) cells are large, non-phagocytic, granular lymphocytes that kill abnormal host cells and comprise 5-10% of circulating lymphocytes.
• Innate lymphoid cells are found in tissues like skin, lungs, and the gastrointestinal tract; respond to signals from infected or injured tissues, release cytokines, and promote immune responses.
• Natural killer cells are a type of innate lymphoid cell, found in tissues and circulating through the blood.
• Lymphocytes and plasma cells are responsible for adaptive immune responses.
• Lymphocyte cells include mononuclear and a granular morphology

Leukocyte Development and Hematopoiesis

• White blood cells circulate via lymphatic and blood systems.
• White blood cells in humans are called leukocytes.
• Hematopoiesis, the process of red and white blood cell development, starts in the embryonic yolk sac, then transitions to hematopoietic stem cells in the bone marrow
• Primary lymphoid organs are tissues associated with leukocyte origin.
• Secondary lymphoid organs are tissues associated with leukocyte development and maturation.
• The lymphatic system connects primary and secondary lymphoid organs for communication.
• After birth, the bone marrow becomes the major site for hematopoiesis.
• Little to no hematopoiesis occurs in the liver and spleen at birth and throughout adulthood.

Pluripotent Hematopoietic Stem Cells (HSCs)

• HSCs give rise to lymphoid or myeloid progenitor cells.
• Progenitor cells lose self-renewal capacity and commit to a single cell lineage.
• Lymphoid progenitor cells produce T cells, B cells, and plasma cells.
• Myeloid progenitor cells produce erythrocytes, eosinophils, basophils, neutrophils, and monocytes.
• Only lymphocytes (T, B, and plasma cells) are antigen-specific and possess diversity, specificity, memory, and non-self recognition.
• Losing self-renewal means progenitor cells cannot indefinitely divide or revert to an undifferentiated state, but are committed to a specific developmental pathway.
• Pluripotent Hematopoietic Stem Cells (HSCs) are master stem cells found in the bone marrow, self-renew, and differentiate into all blood cell types.
• Progenitor Cells are more specialized than HSCs, committed to lymphoid or myeloid lineages.
• Lymphoid progenitor cells give rise to B cells, T cells, and NK cells.
• Myeloid progenitor cells give rise to red blood cells, platelets, and myeloid leukocytes (neutrophils, eosinophils, basophils, monocytes).
• Loss of Self-Renewal means progenitor cells can only divide a limited number of times and cannot return to a stem cell state.
• Specialization is critical for controlled production of blood cells needed for the body’s functions.

Lymphopoiesis

• Lymphopoiesis generates diverse lymphocytes with unique antigen receptors, eliminates self-reactive lymphocytes and allows non-self-reactive lymphocytes to mature.
• Hematopoietic stem cells mature into common lymphoid progenitor cells, which then become B or T cells.
• B cells develop into immature B cells in the bone marrow and then complete maturation into antibody-secreting plasma cells in the lymph nodes and spleen.
• T cells migrate to the thymus and become thymocytes, where they mature into T cells (T for thymus).
• Common lymphoid progenitors leave the bone marrow to mature in the thymus.
• Thymus involution is the shrinking and functional decline of the thymus gland with age.
• The thymus is essential for T lymphocyte (T cell) development and maturation.
• During early life, the thymus is highly active, then begins to shrink in adolescence, replaced by fat.
• By middle age and beyond, the thymus has very little remaining active tissue.
• Thymic involution leads to decline in new T cell production, resulting in a weaker immune system, making older adults more susceptible to infections, cancers, and reduced vaccine efficacy.
• Involution is normal, age-related affected by decrease in thymic hormones and can be accelerated by chronic stress, infections, or health conditions.
• Thymic involution contributes to immunosenescence.

Lymphocyte Development

• Epitope-specific T cell and B cell receptors (TCRs and BCRs) are randomly generated in thymus- and bone marrow–derived lymphocytes by gene rearrangement.
• There is a selection mechanism that removes cells that react with self epitopes before they become functional.
• The adaptive immune system regulates lymphocyte development to prevent maturation of self-reactive T and B cells.
• A common lymphoid precursor (CLP) of lymphocytic lineage cells differentiates within the thymus (T cell lineage) or remains in the bone marrow (B cell lineage).
• T lineage cells differentiate along developmental pathways: αβ TCRs, γδ TCRs, and those sharing NK cell functional properties.
• Cells exported from the thymus are differentiated by TCR diversity, geographic distribution, and responses to epitopes.
• B cell lineages, B-1 and B-2 cells, can be distinguished by the same characteristics as T cell subgroups.

Antigens and Antibodies

• An antigen is a molecule on a pathogen's surface or any substance the body thinks is foreign.
• An antibody is a Y-shaped protein made by immune cells to lock onto antigens.
• Antibodies bind to antigens, marking the pathogen (or other foreign invader) so the immune system can destroy it.
• Binding might neutralize the pathogen, flag it for destruction by immune cells, or trigger immune processes.

Antibody Production and Secretion

• A pathogen enters the body and displays antigens on its surface
• B cells have receptors that can bind specific antigens and get activated when this occurs
• A helper T cell helps the B cell fully activate and multiply
• The B cell transforms into a plasma cell and pumps out antibodies into the bloodstream and tissues.
• Antibodies seek out, bind to, neutralize, or mark for destruction.
• Without antibodies, the immune system would not be able to target and eliminate invaders and infections could spread unchecked.

T Cell Lineage

• T cell precursors (prothymocytes) migrate to the thymus, attracted by thymic molecules like lymphotactin.
• Upon entering the cortical region, prothymocytes lack TCRs, CD3, CD4, and CD8 surface molecules and are now properly called thymocytes.
• Newly arrived thymocytes rapidly acquire TCRs, CD3, CD4, and CD8 molecules.
• Thymocytes must pass selective tests as they migrate from the thymic cortex to the medulla.
• Only 1-5% of thymocytes exit the thymus as T cells.
• 95-99% leave before selection (e.g., γδ T cells) or undergo apoptosis.
• The bilobed thymus is populated by lymphocytes, organized into a cortex and medulla
• Epithelial reticular cells (dendritic cells, macrophages, and epithelial cells) interact with thymocytes as they complete their education
• Epithelial reticular cells express major histocompatibility molecules and secrete hormones associated with thymocyte differentiation.
• Medullary post capillary venules are important for the egress of thymic graduates or T cells from the thymus

αβ T Cell Development

• Prothymocytes enter the subcapsular region of the thymus where they proliferate.
• Newly arrived cortical thymocytes are called double negative (DN) cells because they do not express CD4 or CD8 molecules or TCR or CD3 complex molecules.
• DN cells generate and express αβ TCRs, the associated CD3 complex, and CD4 and CD8 molecules, as well as receptors and adhesion molecules.
• Immature thymocytes that express CD4 and CD8 surface molecules are called double positive (DP) cells.
• TCR stands for T cell receptor, which is found on the surface of T lymphocytes (T cells)
• The TCR recognizes specific antigens that are presented by MHC (Major Histocompatibility Complex) molecules.
• CD4+ T Cells (Helper T Cells) have the CD4 coreceptor and help other immune cells respond to infections.
• CD8+ T Cells (Cytotoxic T Cells) have the CD8 coreceptor and directly kill infected cells.
• DP thymocytes die within 3 to 4 days unless they recognize and bind to major histocompatibility complex (MHC) or to peptide + MHC (pMHC) molecules; this is called positive selection.
• Positive selection eliminates thymocytes incapable of recognizing self MHC.
• Cells that pass positive selection enter the medulla; those that fail undergo apoptosis.
• DP cells whose CD8 molecules have engaged pMHC I cease to express CD4 molecules and become single positive (SP) CD8+ cells.
• Those that are bound to pMHC II stop expressing CD8 and become SP CD4+ cells
• Survivors of positive selection then undergo negative selection at the corticomedullary junction.
• Thymocytes that efficiently bind to self peptides of pMHC I or pMHC II on APCs are potentially autoreactive and undergo apoptotic death.
• Thymocytes that pass both positive and negative selection tests exit the thymus as T cells and enter the circulation through the medullary postcapillary venules.
• Each stage is controlled by substances secreted by epithelial reticular cells regulating gene expression within the thymocytes.
• Secretion of interleukin-7 (IL-7) by epithelial reticular cells activates genes that control the early stages of thymocyte development.
• Failure of early thymocytes to express IL-7 receptors terminates their development.

γδ T Cell Development

• The thymus is also the differentiation site for thymocytes that express γδ TCRs and CD3 complex molecules.
• Many of these cells fail to express CD4 and/or CD8.
• They do not undergo the same positive and negative selective processes as αβ TCR-bearing thymocytes and depart from the thymus shortly after developing their TCR complexes.
• γδ Cells are thought to be a transitional cell type between the innate and adaptive immune systems.
• γδ T cells develop early in embryogenesis before many αβ T cells and migrate preferentially to the respiratory organs, the skin, and the peritoneal cavity.
• They use a very limited set of V, D, and J genes, and are limited in their recognition repertoire compared to αβ T cells.
• They respond more quickly than do αβ T cells, but they do so without generating memory.

NKT Cell Origin

• Natural killer T (NKT) cells are a T cell subset that share characteristics with NK cells.
• They express surface markers and receptors found on NK cells, but undergo some development in the thymus and express TCRs generated by DNA rearrangement and junctional diversity.
• NKT cells express TCRs that are limited in repertoire and are specific for lipids, glycolipids, and a few types of peptides.
• Their TCRs have an unusual restriction pattern.
• Although they may be either CD4+ or CD4+CD8+, they specifically recognize epitopes presented by a “nonclassical” MHC class I molecule called CD1d.
• The nonclassical class I molecules appear to present epitopes (often nonpeptide in nature) to T cells other than the most abundant αβ type.

B Cell Lineage

• Progenitors of immunoglobulin-producing cells are found in the yolk sac by the 3rd week of human development, in the fetal liver by the 8th week, and in the bone marrow by approximately the 12th week of gestation.
• B cells synthesize and display immunoglobulin on their cell surfaces as BCRs
• The bone marrow contains connective tissue, blood vessels, fat, and cells, including hematopoietic stem cells.
• Lymphoid cells committed to the B cell lineage remain within the bone marrow for development.
• The earliest cell committed to the B cell lineage is the pre–pro-B cell (Fraction A), which expresses Igα and Igβ BCR accessory molecules, arising from a common lymphoid progenitor (CLP).
• Immunoglobulin DJ gene joining and cytoplasmic expression of surrogate light chain (SLC) occurs at the early pro-B cell (Fraction B) stage followed by VDJ gene joining and cytoplasmic SLC expression at the late pro-B cell (Fraction C) stage.
• The early pre-B cell (Fraction C′) stage is characterized by the surface expression of pseudo-IgM (rearranged μ heavy chains plus SLC) and is accompanied by cell proliferation.
• At the late pre-B cell (Fraction D) stage, immunoglobulin light chain kappa (κ) or lambda (λ) genes rearrange, and their products (κ or λ light chains) replace the SLCs.
• Immature B cells (Fraction E) express μ heavy chains plus κ or λ light chains on their cell surfaces.
• Mature B cells (Fraction F) coexpress IgM and IgD on their cell surfaces.
• As they pass through the developmental stage, B cell progenitors, like thymocytes, express molecules and receptors necessary for migration and interaction with other cells.
• Some attributes (e.g., DNA recombinase expression) are lost by the time cells reach the immature B cell (Fraction E) stage.
• If the IgM on the developing cells binds to epitopes they encounter in the bone marrow, such cells undergo apoptotic death to prevent production of autoreactive B cells.

B-1 and B-2 B Cells

• Conventional B cells (B-2 B cells) are widely distributed throughout the body, require interaction with T cells for their activation and proliferation, and are replaced from the bone marrow throughout adult life.
• The range of epitopes that can be recognized by B-2 B cells is vast.
• Upon repeated antigen exposure, B-2 B cells respond quickly with increased antibody quantity and quality, often by “fine-tuning,” the affinity of the antibody produced (affinity maturation).
• B-2 B cell responses are often accompanied by a change in immunoglobulin isotype.
• More IgD than IgM is expressed on the surfaces of mature B-2 (Fraction F) B cells.
• Appearing early in embryogenesis, B-1 B cells, arise from the fetal liver by the eighth gestational week and might represent a transitional type of lymphocyte that bridges the innate and adaptive immune systems.
• The B-1 B cell repertoire is quite limited in comparison to that of B-2 cells.
• B-1 BCRs and B-1 B antibodies are often directed against conserved microbial antigens (e.g., carbohydrates).
• Most, if not all, natural antibodies (e.g., IgMs directed against the A and B blood groups that exist in the absence of known immunization) are of B-1 B cell origin.
• B-1 B cells are found predominantly in tissues that are potential portals of microbial entry (e.g., the peritoneal cavity and respiratory tract) and are a self-renewing population within these tissues.
• They show little if any immunologic memory, limited isotype switching, and limited repertoires, but they contribute greatly to protective immunity.
• More than half the IgA secreted into the mucosa is of B-1 origin.

Review Questions

• DiGeorge syndrome affects the thymus, inhibiting T cell development and function, which impairs B cell responses due to T cell dependence.
• Negative selection of T cells occurs in the thymus as they move from the thymic cortex into the thymic medulla.
• T cell precursors migrate from the bone marrow to the thymus in response to lymphotactin.
• Failure of thymocytes to express IL-7 receptors results in apoptotic cell death.
• γδ T cells migrate preferentially to respiratory organs, skin, and peritoneal cavity.
• NKT cells express TCRs generated by DNA rearrangement and junctional diversity.
• Pre–pro-B cells express Igα and Igβ BCR accessory molecules.
• B-1 B cells function in innate-related immune responses.

T Cell Maturation

• T cell maturational stages can be determined by the extent of thymic education. and fall into three maturational stages, cells that express alpha beta T cell receptors, or TCR2 cells that express Gamma Delta TCRs and those cells that maintain surface markers of NK cells.
• Hematopoietic stem cells differentiate into CLP cells, leave the bone marrow, migrate through the blood, and enter the thymus.
• CLPs (now T cell precursors) undergo a selection process in the thymus.
• Pro T cells are double negative because they lack TCR, CD3, CD4, CD8 surface markers.
• Pre T cells are presented with peptides with MHC class one or two complex from local cortical epithelial cells in the thymus
• T cells that bind MHC class one or MHC class two differentiate into positive CD, eight cytotoxic T cells or CD 4t helper cells.

T Cell University

• T cells are stringently evaluated in the thymus leading to graduation into different career paths (tissues) throughout the body.
• Only 1 to 5% of thymocytes graduate as T cells.
• Alpha, beta T cells express a TCR, CD three and either CD four or CD eight surface receptors along with cell-cell adhesion molecules.
• No mature surface markers can be identified on the surface of HSE, CLP or prothymocytes prior to entering the thymus.
• Thymocytes that have been educated in the thymus could develop Gamma Delta, TCRs, CD, three receptors and exit the thymus early in development.
• Ultimately, single, positive thymocytes need to recognize peptides presented on MHC, class one or two molecules, before differentiating into mature T cells with unique surface receptors.

Gamma–Delta T Cells

• Gamma-delta T cells express TCRs made of γ (gamma) and δ (delta) chains, whereas alpha-beta T cells express TCRs made of α (alpha) and β (beta) chains.
• Gamma-delta T cells are involved in early immune responses and migrate to peripheral tissues (e.g., skin, respiratory tract, peritoneal cavity) during early embryogenesis without the rigorous selection process of alpha-beta T cells.
• Gamma-delta T cells monitor for infection or tissue damage.
• Gamma/delta T cells are often considered part of the innate immune system
• They can recognize certain stress signals or non-peptide antigens and act quickly akin to innate immune cells

B Cell Maturation

• B cell maturational stages occur in the bone marrow.
• Bone marrow derived lymphocytes or B cells generate immunoglobulins and display them on their surface, along with B cell receptors or BCRs, and remain in the bone marrow..
• B cells, like T cells, arise from CLPs and quickly differentiate into the B cell lineage
• Early B cells are pre pro B cells, expressing Ig-alpha and Ig-beta genes to develop the mature BCR molecule.
• Pro B cells bind to stromal cells, which activates an IL-17 signal modulated by C kit and stimulate B cells to differentiate into pre B cells that express rearranged IG light chains.
• Immature and mature B cells express heavy chains plus kappa or lambda genes, and eventually Express cell surface IgM and IgD, respectively.
• B cell development can be divided into three broad stages: generation of mature, immunocompetent B cells, activation of B cells and differentiation of B cells into plasma cells. The markers distinguishing B cell lineage is antigen-independent Pre-Pro B cells originate from CLPs and express IG alpha and iG beta the beginnings of the BCR.
• Pro-B cells express a surrogate light chain or SLC, followed by pseudo IgM plus SLC during the early pre-B cell.
• Two subsets of B cells emerge during B cell maturation: B, 1b cells develop during fetal life and make up 5% of the total population, and B, 2b cells are the dominant subtype that develop surface IgM and IgD.
• B, 1b cells contribute to innate immunity

Additional Review Questions:

• Thymic involution leads to a reduction in the production of new T cells, which has implications for susceptibility to infections, vaccine responsiveness, and the development of certain immune-related conditions in older individuals.
• Proliferation of large pre-B cells results in the production of many B cells with the same VH chain but different antigen specificities due to different VL regions.
• Pre pro b cell (express Ig-alpha and Ig-beta genes), Pro-B cells express a surrogate light chain, immature B cells express IgM and Mature B cells co-express IgM and IgD c-Kit Role in Pro-B Cells: Role in pro-B cells Pro-B cells express c Kit, SCF binds to c-Kit and triggers intracellular signaling pathways that promote the proliferation and differentiation of pro-B cells

Surrogate Chain

• The surrogate light chain (SLC) in early B cell development (pre-B cell stage) is involved in the formation of the pre-B cell receptor (pre-BCR).
• It tests whether B cells develop functional B cell receptors (BCRs).
• Its expression and interaction with the heavy chain enable the B cell to verify that the heavy chain is capable of binding to an antigen, which is essential for the B cell to proceed with further development.

Lymphoid Tissues and Organs

• Leukocytes may be distributed as single cells in the tissues and circulation, as lymphoid accumulations, or within lymphoid organs
• Lymphocytes develop within the primary organs: thymus and bone marrow.
• The secondary lymphoid organs trap and concentrate immunogens and provide sites where circulating immune cells can make contact with each other.
• Specific immune reactions are initiated with the interactions that occur in secondary lymphoid organs.
• The primary lymphoid organs, the thymus and bone marrow, serve as lymphocyte educational centers.
• Although all lymphocytes originate within the bone marrow, those destined to become T cells are sent at an early age to develop further in the thymus.
• Lymphocytic lineage cells that remain within the bone marrow are destined to become B cells. -Stromal cells within the thymus and bone marrow closely regulate the development of T and B lymphocytes.
• Stem cells of bone marrow origin called prothymocytes are committed to the T cell lineage and migrate via the circulation to the thymic cortex before becoming cortical thymocytes
• Double positive (DP) thymocytes encounter positive selection, the recognition of MHC class I (by CD8) or MHC class II (by CD4).
• Tremendous numbers of thymocytes are processed by the thymus, but fewer than 5% of the thymocytes successfully complete this process.
• Lymphocytic lineage cells develop their BCRs by DNA rearrangement, express auxiliary molecules such as Igα and Igβ, and display IgM on their surfaces prior to leaving the bone marrow.
• These B cells would be self-reactive and binding of BCRs triggers the cells bearing them to undergo apoptotic death
• The secondary lymphoid tissues function as filtration devices removing foreign matter, dead cells, and protein aggregates from the circulation.
• Specialized regions of the vasculature, called high endothelial venules, permit the movement of cells between the blood and the tissues or organs through which they are passing
• The major secondary lymphoid organs are the spleen and lymph nodes.
• The tonsils and Peyer’s patches also act as secondary lymphoid accumulations.
• Lymph nodes function as filters to purify lymph, the fluid and cellular content of the lymphatic circulatory system, and provide sites for mingling of lymphocytes, monocytes, and dendritic cells for initiation of immune responses.
• Anatomically, a lymph node is divided into the cortex and medulla.
• The reticulum or framework of the organ is composed of phagocytes and specialized kinds of reticular or dendritic cells.
• The superficial cortex contains mostly B cells.
• The deep cortex is the T cell–rich area.
• Circulating cells enter the outer cortical area through blood or lymphatic vessels and then filter down through the deep cortex and into the medulla before leaving the lymph node and moving on
• The largest lymphoid organ, the spleen clears particulate matter from the blood and concentrates bloodborne antigens and microbes.
• The spleen is divided into the lymphocyte-rich white pulp and erythrocyte-rich red pulp.

Lymphatic Circulatory System

• Leukocytes and their products use the cardiovascular system and the lymphatic circulatory system, an extensive capillary network that collects lymph from various organs and tissues.
• Lymphatic vessels within small intestine villi, designated lacteals, contain chyle, produced by digestion.
• The lymphatic capillaries drain into large lymphatic vessels that drain into lymph nodes for filtration.
• Ultimately, the lymphatic trunk vessels join to form the thoracic duct that conveys lymph into the subclavian artery.
• Brain lymphatic vessels connect the brain and the immune system.
• The brain lymphatic system drains interstitial fluid from the brain to nearby lymph nodes to clear waste and maintain water balance
• Impaired drainage of proteins via lymphatic vessels may be involved in the pathogenesis of Alzheimer disease.

Thymus

• The thymus generates and selects a population of T cells to protect the body from infection.
• Each lobe is surrounded by a capsule that is further divided into lobules and separated by connective tissue.
• The thymus is a flat, bilobed organ situated above the heart and has an outer compartment with immature thymocytes and an inner compartment with mature thymocytes.
• The cortex and medulla are criss-crossed by a stromal cell network derived of bone marrow, epithelial cells, dendritic cells, and macrophages.
• The cortex consists of immature thymocytes, branched cortical epithelial cells and few macrophages.
• The medulla consists of mature thymocytes, medullaris epithelial cells and larger populations of macrophages and dendritic cells
• Stromal cells are critical for T cell maturation and selection.
• Key stromal cells involved in this process include cortical thymic epithelial cells (cTECs), medullary thymic epithelial cells (mTECs), macrophages and dendritic cells
• cTECs cells help in the positive selection of T cells by presenting self-peptides to developing T cells (thymocytes) through MHC molecules.
• mTECs cells present self-antigens to thymocytes for negative selection in the thymus aids in the removal of apoptotic cells during thymocyte selection

Central Tolerance

• The overall principle that prevents the immune system from attacking the body’s own cells
• Central tolerance is where T cells undergo training in the thymus by by encountering and checking against self-antigens (self-cells) to see if they can tell the difference between self and non-self.
• Negative selection makes ensures that T cells don’t react too strongly to self-cells by eliminating them to ensure that only T cells that don’t react to self are allowed to graduate and enter circulation.
• Size decline of the thymus results in dysfunction.
• Thymic size is associated with thymic function.
• Age declines efficiency declining T cell development.
• After puberty, the thymus atrophies with a significant decrease in cortical and medullary cells, and the aged dependent thymus contains a lot of fat.
• Immature thymocytes influence the arrangement of thymic epithelial cells, and in return epithelial cells provide a critical microenvironment for T cell survival.
• Most T cell development takes place in the cortex beginning in the subcapsular region before differentiation to positive thymocytes occurs further down the cortes,

Positive T Cell Selection

• The recognition of self MHC molecules ensures circulating T cells are restricted to recognize MHC molecules of the host body.
• Only immature T cells that are able to recognize self MHC molecules can generate effective T cells that are critical for adaptive immunity.
• Double positive thymocytes must bind to an MHC molecule or to foreign antigen combined with self MHC molecules, or they will be eliminated.
• Differentiation results in double positive thymocytes express CD four, CD eight, and a TCR with accompanying CD three complex.
• Double positive thymocytes that effectively bind MHC class two receive a protective signal inhibiting apoptosis and cease expression of CD eight.
• Double positive thymocytes that effectively bind MHC, class one receive a protective signal and cease expression of CD four becoming single positive CD eight thymocytes.
• Only 2% of all thymocytes survive due to the need for the TCR to specifically recognize foreign antigen plus self MHC molecules, or they fail positive selection.
• Thymocytes that survive positive selection undergo negative selection to ensure self tolerance and reduce autoimmunity.
• High binding to cell peptides causes apoptosis

T Cell Gestation

• Thymocytes (C3 marker) leave the thymus early during gestation without undergoing selection, whereas alpha/beta T cells ( undergo positive and negative selection) arrive later.
• gamma/delta T cells are present in higher amounts during early gestation, are involved in early immune responses and considered part of the innate immune system

Major points of T Cell Selection:

• Alpha/beta lineage thymocytes undergo an extensive selection process
• Positive selection ensures only thymocytes that bind self MHC survive.
• Negative selection eliminates single positive thymocytes that express high affinity receptors for cell antigen and/or cell MHC
• The delta/gamma lineage exits the thymus, without undergoing positive or negative selection.

Thymic Involution

• Over time, increased adipose tissue crowding the thymus leads to an increased decline in T cell development and decline of cell-mediated immunity.
• The thymus is most active during childhood and adolescence
• Increased Accumulation of Memory T Cells
• A less efficient selection process in the aging thymus can allow autoreactive T cells to escape into the circulation

T Cell differentiation

• Developing T cells differentiate into CD4+ or CD8+ single-positive through precise interactions with self-peptides presented by MHC complexes
• Incoming lectures will provide more details of the different steps of T cell maturation in the thymus.

DiGeorge Syndrome (DGS)

• DiGeorge syndrome affects T cell maturation, MHC restriction, causes low T cells, recurrent infections, and heart defects.
• With DGS the thymus is either absent or small
• Immunologists assess T cell count in patients before administering vaccines such as rotavirus, measles, mumps, rubella virus vaccine, and the varicella (chickenpox) vaccine.
• With DGS B cell difficulty with immunoglobulin and responses
• Two common psychiatric conditions of adolescents and adults with DGS: schizophrenia and bipolar disorder

T Cell Effector

• T cell effector functions require the interaction of a T cell with a target cell displaying specific antigen.
• CD four cells are restricted to class two MHC molecules, whereas CD eight cells are restricted to recognition of class one MHC molecules,
• CD8+ T cells function as cytotoxic T cells and are MHC class one restricted and kill cells that display peptide particles at cytosolic pathogens, most viruses, bound to MHC class one molecules
• CD4+ T cells function as T helper cells and are MHC class two restricted recognize fragments of antigens degraded with intracellular vesicles presented by APCs of exogenous antigens.

Effector T Cells

Different effector T cells are specialized to deal with pathogens

• The pattern of cytokine expression defines subsets of CD four and CD 8t cells
• Interaction between APCs and T cells influences T cell effector subpopulations
• Subpopulations of T cells after interacting with antigen and MHC class determine cytokine levels and resulting outcomes.
• Th1 cells secrete interferon gamma and activate T cytotoxic effectors and generate a pro-inflammatory response
• Th17 cells promote resistance to extracellular bacteria and fungi, provide protection at mucosal surfaces and promote autoimmune inflammation
• Th2 cells secrete IL-4 and anti inflammatory and assist in fighting parasites and assist B cells to secrete antibodies and humoral immunity
• Th3 and TR, one subpopulations. suppress inflammation Cytokine expression defines the subsets of CD four and CD 8t cells Cytokine expression defines the subsets of CD four and CD 8t cells Cytokine expression defines the subsets of CD four and CD 8t cells
• Treg Cells: autoimmunity, activity of other immune and cytokines Transforming
• IL-4 promotes a anti inflammatory, regulates cytotoxic markers and promotes B cell activation

Review: T Cell Effector

• The key cells of the adaptive immune response: B and T cells. T helper cells express CD four and cytotoxic T cells express CD eight.

Determined immune responses: determined by the cytokines the T cell is exposed to within an immune synapse.

• Th1 cells fight intracellular infections and secrete tumor necrosis and interferon.
• Th2 cells fight parasites
• Th17 cells fight fungal and bacterial infections. in delayed hypersensitivity, antibody production, inflammation, immunosuppression, regulatory cytotoxicity.

B cell Development

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Overview of lymphoid lineage cells, including B lymphocytes in bone marrow, T cells in the thymus, and natural killer (NK) cells. Covers innate lymphoid cells and their role in immune responses. Lymphocytes and plasma cells facilitate adaptive immunity.