Cellular Immunity: T Cells and APCs

Introduction to Cellular Immunity

• Immunity developed by cell-mediated response is known as cellular immunity or T cell immunity
• Cellular immunity involves T lymphocytes, macrophages, and natural killer cells
• Cellular immunity does not involve antibodies
• It is the major body defense against micro-organisms
• It is responsible for delayed allergic reactions and tissue transplant rejection
• T lymphocytes provide cell-mediated immunity, activated upon contact with antigens
• Invading antigen-carrying substances can be microbial or non-microbial
• Antigenic materials are released from invading organisms and presented to helper T cells by antigen-presenting cells

Antigen-Presenting Cells (APCs)

• APCs are of 3 types: macrophages, dendritic cells, and B lymphocytes
• Macrophages are the major antigen-presenting cells

Macrophages

• Macrophages are large phagocytic cells that digest invading organisms to release the antigen
• They are usually present with lymphocytes in almost all lymphoid tissues

Dendritic Cells

• Dendritic cells are non-phagocytic and classified into 3 types
• Dendritic cells in the spleen trap antigens in the blood
• Follicular dendritic cells trap antigens in lymph nodes
• Langerhans dendritic cells in skin trap organisms in contact with the body surface

B Lymphocytes

• B lymphocytes present antigen to cells
• They function as both antigen-presenting and antigen-receiving cells
• B lymphocytes need activation by helper T cells, making them the least efficient APCs

Antigen Engulfment and HLA

• APCs engulf foreign micro-organisms through phagocytosis by macrophages, trapping by dendritic cells, and pinocytosis by B cells
• Antigens are digested into small peptide products
• Antigenic peptides move to the surface of APCs and bind with human leukocyte antigen (HLA)
• HLA is a genetic material in class II major histocompatibility complex (MHC) molecules on the surface of APCs

MHC & HLA

• MHC is a large molecule on the short arm of chromosome 6
• It consists of a group of genes involved in the immune system
• MHC has over 200 genes, including HLA genes which are made up of small molecules
• MHC encodes antigen-presenting proteins on the cell surface
• MHC molecules and HLA genes are used interchangeably

MHC Molecule Classes

• MHC molecules in humans are divided into two classes
• Class I MHC molecules are found on every cell in the body
• Class I MHC molecules present endogenous antigens to cytotoxic T cells
• Class II MHC molecules are found on antigen-presenting cells
• Class II MHC molecules present exogenous antigens to helper T cells

Antigen Presentation to T Cells

• Antigen presenting cells present their class II MHC molecules together with antigen-bound HLA to helper T cells.
• Helper T cells recognize the antigen displayed with the help of its own surface receptor protein called T cell receptor.
• This activates helper T cells through a sequence of events

T Cell Activation

• Recognition of antigen initiates a complex interaction between the helper T cell receptor and the antigen, leading to activation
• Simultaneously, macrophages release interleukin-1, which facilitates the activation and proliferation of helper T cells
• Then, activated helper T cells proliferate and enter the circulation for further activity
• The antigen bound to class II MHC molecule activates the B cells to lead to humoral immunity

Helper T Cells

• Helper T cells activate all other T cells and B cells
• There are 2 types of helper T cells: Helper 1 (TH1) and Helper 2 (TH2) cells

TH1 Cells

• TH1 cells are important in cellular immunity
• They secrete interleukin-2 (activates other T cells) and Gamma interferon (stimulates phagocytic activity)
• Gamma interferon stimulates the phagocytic activity of cytotoxic cells, macrophages, and natural killer (NK) cells

TH2 Cells

• TH2 cells are involved in humoral immunity
• They secrete interleukin-4 and interleukin 5 which are concerned with activation of B cells, proliferation of plasma cells, and production of antibodies by plasma cells

Cytokines

• Cytokines are non-antibody proteins released by cells that act as intercellular mediators, especially in immune processes
• They are clinically important as biological response modifiers
• Monokines are produced by mononuclear phagocytes
• Lymphokines are produced by activated T cells, primarily helper T cells
• Interleukins are cytokines, abbreviated as IL with a number

Properties of Cytokines

• Cytokines are produced by cells involved in both natural and specific immunity
• They mediate and regulate immune and inflammatory responses
• Secretion is brief and limited because they are not stored as pre-formed molecules, synthesis is initiated by new short-lived gene transcription, and mRNA is short-lived
• Cytokine production happens only as needed
• Cytokines are pleiotropic, as many individual cytokines are produced by many cell types and act on many cell types
• Cytokines often influence the synthesis of other cytokines, producing cascades, or enhancing or suppressing production
• Cytokines exert positive or negative regulatory mechanisms for immune and inflammatory responses
• They influence the action of other cytokines, with effects that can be antagonistic, additive, or synergistic
• Cytokines bind to specific receptors on target cells with high affinity

Cytokine Responses

• Cells can respond to a cytokine in three ways
• Autocrine, where the same cell that secreted the cytokine responds
• Paracrine, where a nearby cell responds
• Endocrine, where a distant cell responds through circulation
• Cellular responses to cytokines are generally slow (hours) and require new mRNA and protein synthesis

Cytokine Function

• Some cytokines mediate and regulate natural immunity: Tumor Necrosis Factor (TNF), Interleukin-1 (IL-1), Chemokines, Interleukin-10, and Interferon-gamma (IFN-gamma)
• Some cytokines mediate and regulate specific immunity: Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-5 (IL-5), Interleukin-10 (IL-10), and Interferon-gamma (IFN-gamma)
• Some cytokines stimulate of hematopoiesis: Interleukin-3 (IL-3) and Colony-Stimulating Factors (CSFs)

Tumor Necrosis Factor (TNF) Cytokine

• Functions by mediating and regulating in natural immunity also called TNF-gamma
• TNF is produced by activated macrophages
• It is the most important mediator of acute inflammation in response to Gram-negative bacteria and other infectious microbes
• It mediates the recruitment of polymorphonuclear leukocytes (PMNs) and monocytes to the site of infection

TNF Effects

• TNF stimulates endothelial cells to express new adhesion molecules for PMN and monocytes, making the cell surface sticky
• TNF stimulates endothelial cells and macrophages to produce chemokines that induce leukocyte chemotaxis and recruitment
• It acts on the hypothalamus to produce fever
• It promotes the production of acute phase proteins by the liver

Interleukin-1 Cytokine

• IL-1 is produced by activated macrophages
• IL-1 effects are similar to those of TNF

Chemokines Cytokine

• Chemokine is a contraction of chemotactic cytokines
• There are a large family of substances (more than 50) produced by different leukocytes and tissue cells
• They recruit leukocytes to sites of infection
• They play a role in lymphocyte trafficking

Interleukin-10 Cytokine

• Produced by activated macrophages
• Acts as an inhibitor of activated macrophages by blocking the production of TNF

Interleukin-2 Cytokine

• Functions by mediating & regulating in a specific manner
• IL-2 is produced mainly by helper T cells (CD4+), less by cytotoxic T cells (CD8+)
• Promotes T cell division and increases production of other cytokines
• It has autocrine functions on T cell proliferation

Interleukin-4 Cytokine

• IL-4 is produced mainly by Th2 subpopulation of helper T cells (CD4+)
• Th2 cells are required for antibody production by B cells
• It stimulates immunoglobulin class switching to the IgE isotype
• It stimulates development of Th2 cells from naive CD4+ T cells, and promotes growth of differentiated Th2 cells
• IgE is involved in eosinophil-mediated elimination of helminths and arthropods

Interleukin-5 Cytokine

• IL-5 is produced mainly by the Th2 subpopulation of helper T cells (CD4+)
• IL-5 promotes the growth and differentiation of eosinophils and activates mature eosinophils
• IL-4 and IL-5 function together
• IgE opsonizes helminths that then bind to eosinophils which upon activation kill the helminth

Interferons (IFN)

• These are three groups: IFN-alpha, IFN-beta, and IFN-gamma
• IFN-alpha has twenty variants produced by leukocytes in response to viruses
• IFN-beta is a single protein produced by fibroblasts and other cells in response to viruses
• Both IFN-alpha and IFN-beta inhibit viral replication and increase expression of class I MHC on cells

IFN-Gamma Cytokine

• IFN-gamma is produced by the Th1 subpopulation of helper T cells (CD4+), cytotoxic T cells (CD8+), and NK cells
• Th1 cells eliminate pathogens residing intracellularly in vesicular compartments
• IFN-gamma functions in both natural and specific immunity
• In natural immunity, IFN-gamma enhances the microbicidal function of macrophages through formation of nitric oxide and reactive oxygen intermediates (ROI)

IFN-Gamma Specific Immunity

• IFN-gamma stimulates the expression of class I and class II MHC molecules and co-stimulatory molecules on antigen-presenting cells
• IFN-gamma promotes the differentiation of naive helper T cells into Th1 cells
• IFN-gamma activates polymorphonuclear leukocytes (PMN) and cytotoxic T cells and increases the cytotoxicity of NK cells

Transforming Growth Factor (TGF-beta)

• TGF-beta is an inhibitory cytokine produced by T cells, macrophages, and other cell types
• It inhibits proliferation and differentiation of T cells
• It inhibits activation of macrophages
• TGF-beta acts on PMN and endothelial cells to block the effects of pro-inflammatory cytokines

Interleukin-3 Cytokine

• Interleukin-3 functions as a stimulator of hematopoiesis
• It is produced by helper T cells
• It promotes growth and differentiation of bone marrow progenitors

Colony-Stimulating Factors (CSFs)

• Functions as a stimulator of hematopoiesis
• Produced by T cells, macrophages, endothelial cells, and fibroblasts

CSF Types

• Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes growth and differentiation of bone marrow progenitors
• Macrophage colony-stimulating factor (M-CSF) is involved in the development and function of monocytes/macrophages
• Granulocyte colony-stimulatory factor (G-CSF) stimulates the production of PMN

Cytotoxic T Cells

• Activated by helper T cells, these cells circulate through blood, lymph, and lymphatic tissues to destroy invading organisms by attacking them directly
• Mechanism of action: receptors on the cytotoxic T cell membrane bind antigens tightly
• Then enlarge and release cytotoxic substances such as lysosomal enzymes to destroy the invading organisms enabling the destruction of a large numbers of microorganisms

Suppressor T Cells

• Suppressor T cells are also called regulatory T cells
• They suppress the activities of killer cells and helper T cells
• They prevent killer T cells from destroying the body's own tissues along with invading organisms

Memory T Cells

• Antigen-activated T cells that do not enter the circulation but remain in lymphoid tissue
• These memory T cells migrate to various lymphoid tissues throughout the body
• memory T cells identify the organism and immediately activate the other T cells when the body is exposed to the same organism a second time
• Response is more powerful, rapidly destroying the organism

T-Cell Deficiency

• Presents with severe, protracted infections
• Infections caused by viruses, fungi or rarely detected organisms such as Pneumocystis carinii and Cryptococcus
• Administration of live vaccines and blood products become contraindicated
• Classified into primary/congenital and secondary/acquired

Primary T-Cell deficiencies

• Rare, often severe and usually present soon after birth
• Includes total or partial T-cell depletion or loss of function

Secondary (acquired) T-Cell deficiencies

• Associated with metabolic disorders, diabetes mellitus, undernutrition, drug abuse, or auto-immunity, and immunosuppressive treatment or radiation
• Relatively common and present at any age

Conclusion

• T cells play important roles in cellular immunity
• B cells are concerned primarily with immunoglobulin synthesis and humoral immunity
• Both T and B cell functions may however be affected in SCID, which is severe combined immunodeficiency syndrome