T Lymphocytes: Development and Function

Introduction

• Lymphocytes T (LT) are mononucleated cells of lymphoid origin.
• T lymphopoiesis occurs in the thymus.
• LT are the support of adaptive cellular immunity.
• They express specific surface markers that distinguish them from B lymphocytes (LB).
• They recognize the antigen (Ag) presented by antigen-presenting cells (APCs) in association with MHC molecules.
• They include different subpopulations.
• The stages of intra-thymic selection allow the generation of the T repertoire.
• Mature lymphocytes are educated to recognize and tolerate self, and to recognize and reject non-self.
• They leave the thymus to localize in secondary lymphoid organs at the level of T-dependent areas.
• They access these areas via the bloodstream.
• LT that have not yet encountered the antigen are called naive LT.

Development of T Cells

• LT originate from a common lymphoid progenitor (CLP) located in the bone marrow.
• CLP comes from the pluripotent hematopoietic stem cell, which is at the origin of all blood cell lines.
• The CLP differentiates into B progenitor, T progenitor, and NK cells.
• The T lymphoid progenitor leaves the bone marrow to go to the thymus.
• In the thymus, lymphoid cells are called thymocytes, and they pass through several stages of differentiation/maturation.
• During these stages, they acquire differentiation markers, which are important molecules expressed on the membrane.
• Clusters of Differentiation (CD) are lineage-specific.
• Important markers include CD2 (pan T), CD3 (associated with TCR), CD4, and CD8, as well as the TCR/CD3 complex.

T Cell Ontogeny

• T cell ontogeny involves stages of differentiation in the thymus: Double Negative (DN), Double Positive (DP), and Simple Positive.

Double Negative (DN) Stage

• Genes undergo rearrangement of δ and γ(+++), with β genes in germline configuration.
• Rearrangement of δ and γ genes is completed, and rearrangement of β genes is initiated.
• Gene rearrangements are halted.
• Phenotype includes TdT (+), CD117 (+), CD2 (+), CD5 (+), CD7 (+), CD1, CD3 (-), CD4 (-), CD8 (-).
• 5% of cells become T cells with TCR (γδ).

Thymocytes with TCR γδ (5%)

• Double-negative (CD4-, CD8-) and express NK receptors.
• These cells leave the thymus for the mucous membranes, differentiating into intraepithelial lymphocytes (IEL).
• IEL disseminated among epithelial cells detect stress signals from infected or damaged cells, contributing to their elimination and mucosal immunity.
• Express the phenotype of CD2 (+), CD5 (+), CD7 (+), TCR (γδ)/CD3 (+), CD4 (-), and CD8 (-).
• Recognize cellular antigens (HLA-C, HLA-E, CD1 a,b,c, MIC-A, MIC-B) and soluble antigens (Phosphoantigens).

Thymocytes Double Positive to TCR αβ (95%)

• Express the phenotype CD2 (+), CD5 (+), CD7 (+), TCR (αβ)/CD3 (+), CD4 (+), and CD8 (+).
• Undergo positive selection in the cortex, differentiating into LT with TCR αβ/CD3, either CD4+ CD8- or CD4- CD8+.

Positive and Negative Selection

• Positive selection ensures that T cells can recognize self-MHC molecules.
• Negative selection eliminates T cells that react too strongly to self-antigens.
• Thymocytes interacting with self-MHC with very strong or weak affinity are eliminated by apoptosis or clonal deletion
• Only positively selected thymocytes that interact appropriately with self-MHC survive.
• Saved cells become single positive.
• Thymocytes CD4+ recognize immunogenic peptides presented in association with class II MHC molecules.
• Thymocytes CD8+ recognize immunogenic peptides presented in association with class I MHC molecules.
• Negative selection affects single positive thymocytes, which test their TCR against endogenous peptides.
• These peptides are presented by dendritic cells at the cortico-medullary junction.
• The affinity of the interaction determines the fate of these thymocytes.
• LT with a TCR that recognizes self-peptides with high affinity are eliminated by apoptosis.

Phenotype of Resting LT

• TCR (αβ)/CD3, CD4 or CD8.
• CD2, CD5, CD6, CD7, CD28.
• IL1-R, IL4-R, IL12-R.
• ICAM1, VLA, LFA.
• CMH I.
• Receptors for mitogens: PHA, Concanavaline A.
• Naive LT express CD45 RA, while memory LT express CD45 RO.

TCR Complex

• The TCR complex consists of two modules: the recognition module and the signal transduction module.
• The recognition module is a heterodimer (α, β) with two Ig-like domains, Vα, Cα, VB, and Cβ.
• The signal transduction module is a multimeric CD3 complex formed of monomorphic chains γ, δ, ε, ζ.
• It has intra-cytoplasmic regions with activation motifs (ITAM), which recruit enzymes involved in intracellular signaling.

T Lymphocyte Activation

• Antigen is first taken up by the APC, undergoing intracellular processing called presentation.
• Presentation includes cleavage and degradation of the antigen, selection of immunogenic peptides, incorporation of peptides into the niche of MHC molecules, and expression of the peptide-MHC complex on the surface.
• LT-CPA interaction involves TCR/CD3 binding to MHC/peptide and CD4/CMH II or CD8/CMH I, which emits the first signal of activation.
• Co-activation molecules, like CD28-CD80, CD28-CD86, CD2 - CD58, and LFA1-ICAM1, provide the second signal of activation.
• CD28 provides the major co-stimulation signal for IL2 production, crucial in generating cytotoxic LT (CTL) from differentiated CD8+ LT.
• CD28 and CTLA4 share ligands B7.1 (CD80) and B7.2 (CD86).
• CTLA4 is expressed on activated LT surfaces, peaking on the third day, delivering an inhibitory signal.

Phenotype of Activated LT

• In addition to markers expressed at rest, lymphocyte T activation induces the expression of CMH II, CD25, and CD40 ligand.

Function of LT CD4+ (Helper)

• Naive LT CD4+ secretes a set of cytokines, becoming TH0.
• Depending on the cytokine environment, it differentiates into TH1, which secretes IL2, TNFα, IFNγ, or TH2, which secretes IL4, IL5, IL6, IL10.

T Cell Activation Sequence

• Recognition of the antigen
• Activation
• Clonal expansion
• Differentiation
• Effector functions

CTL Generation

• CTLs are generated to eliminate infected or tumor cells.
• CTLs needs two cells, one T helper and the target

Interaction of CTL and target cell

• The interaction involves the release of performin and granzymes
• The target cell will be destroyed by either lysis or apopotosis

LT-LB Cooperation

• It takes the use of cell adhesion molecules like ICAM, LFA1, CD etc

Activation of LB

• T dependent activation means that the T cell must come along and help.
• Activation requires
• It is necessary for the production of IgE

RI Humoral to IgG

• When the RI is humoral it can only produce IgG

Subpopulations of LT

• Subpopulations are based on phenotype (TCR/CD3 type, CD4/CD8) and function.
• Functional categories include Helper T cells, Effector T cells, Memory T cells, and Regulatory T cells.
• Subpopulation breakdown of T Cells (based on the TCR) includes γδ T cell and αβ T Cells
• Subpopulation breakdown of T Cells (based on the co receptor present) includes CD4 cells and CD8 cells
• HELPER T CELLS include TH1, TH2 and TH17
• The production of cytokines will determine the type of T cell produced