T-Lymphocyte: Development and Differentiation
T-Lymphocyte: Development and Differentiation
- T cell antigen-binding membrane receptor or TCR is the structural and functional hallmark of the total T cell lineage.
- The level of maturation and membrane expression of TCR corresponds to the developmental stage of T lymphocytes.
- There are two basic subsets of T cells bearing distinct TCR molecules. The majority of human T cells expresses a membrane T cell receptor composed of alpha and beta chains (αβ T cells). The rest of the T cells carries membrane TCR of gamma and delta chains (γδ T cells).
- The representatives of αβ T cells settle in all lymphoid tissues and organs, whereas γδ T cells are present within the mucosa of the gastrointestinal tract or respiratory tract. Hence, γδ T cells play the primary protective role within superficial barrier tissues, thus preventing pathogen invasion.
- Early stages of T cell development are followed by the migration of T cell precursors initially from the fetal liver and later after birth from the bone marrow toward the thymus, where the maturation of T cells occurs.
- It should be noted that αβ T cells predominantly arise from the cells migrated from the bone marrow, whilst most of γδ T cells originate from T cell precursors of the fetal liver.
- The thymus is the lymphatic epithelial gland active in the fetal period and in childhood before puberty. Later it undergoes involution, but a part of lymphoepithelial tissue remains active for a long time.
- The thymus is the place of antigen-independent differentiation of primary T cells generally termed as thymocytes. When maturating, they gradually move from cortical to the medullar zones of the thymus. Thymic hormones actively influence T cell maturation.
- Membrane expression of TCR and a certain number of membrane CD molecules reflect the steps of T cell development.
- The earliest pro-T cells express recombinase Rag proteins that stimulate the rearrangement of T cell receptor genes.
- The transition of these cells into pre-T cells is followed by expression of one chain (β or γ) of TCR and membrane CD1, CD2 and CD7 molecules. All these thymocytes initially demonstrate CD4 and CD8 negative phenotype (known as “double-negative” T cells).
- Further differentiation of T cells leads to the membrane expression of complete two-chain TCR molecule with the addition of CD3. These cells also acquire membrane CD4 and CD8 molecules (“double-positive”) T cells.
- At this stage, the whole number of thymocytes bearing membrane TCR undergo the process of positive and negative selection. It occurs by the specific contact of T cells with thymic epithelial cells. In this case, thymic epitheliocytes present the host self-antigens for maturating T cells in complex with the host HLA molecules of I or II class.
- At first T cells bearing TCRs that weakly react with the complex self Ag-self HLA molecule on the membranes of thymic epithelial cells are selected (positive selection). Other non-reacting thymocytes are eliminated by apoptosis. This ensures the recognition of foreign antigen by specific TCR only in the complex with the host HLA molecule (double recognition, HLA restriction).
- On the other hand, the remaining thymocytes that bear TCR with the highest affinity (binding capacity) to the self Ags are also eliminated by apoptosis (negative selection). The deletion of the most powerful autoreactive T cell clones creates the unresponsiveness to the body self-antigens (central tolerance) thus preventing the emergence of autoimmune disorders.
- When the T cell recognizes the antigen in complex with I class HLA, this requires additional binding to co-stimulatory CD8 molecule. And conversely, the recognition of an antigen in complex with II class HLA requires binding to the membrane co-stimulatory CD4 molecule.
- The latter events lead to the transformation of initial double-positive T cells into single-positive “naive” (CD4+) helper or (CD8+) cytotoxic T cells.
- Single-positive T cells migrate toward the peripheral T-dependent zones of lymphoid tissues. When contact with foreign antigen occurs, T lymphocytes initiate antigen-dependent differentiation.
- This leads to the T cell conversion into their final subsets with specialized effector functions. The process of foreign antigen binding stimulates the selection and blast transformation of Ag-specific T cells that results in the proliferation of Ag-specific T cell clones (clonal expansion) and formation of long-living memory T cells.
- The most common T cell markers are TCR, CD2, CD3, and CD7 as well as CD4 for helper cells and CD8 for cytotoxic cells.
- The normal quantity of common T cells is about 60% (50-75%) from the whole blood lymphocytes population.
Subpopulations (Subsets) of T Lymphocytes
- T helpers recognize the processed antigen in complex with HLA-II class molecules by their membrane TCR. As a result, T helpers stimulate proliferation and differentiation of T- and B cells.
- There are 2 major T helper subsets distinguished by their functions – T helper 1 and T helper 2 (Th1 and Th2). They produce the specific combinations of cytokines largely opposite in their activities.
- Co-stimulatory CD4 molecule of T helpers interacts with HLA-II class molecules in the presentation of antigen to T cells.
- Th1 secrete IL-2 and γ-interferon, thus stimulating cell-mediated immunity. Th1 trigger the reactions, defending the host against the broad number of agents, including intracellular pathogens. They activate macrophages, dendritic cells, and cytotoxic lymphocytes thereby promoting inflammation.
- Th2 enhance the activity of B lymphocytes stimulating their transformation into plasma cells and the synthesis of antibodies. They activate immunoglobulin isotype switching resulting in the production of antibodies of all Ig classes including IgE.
- Th2 produce IL-4, IL-5, IL-6, IL-10, IL-13, IL-15 and therefore maintain humoral immune response.
- A special population of T helper cells Th17 is activated by IL-21, IL-23, and TGF-β.
- By production of IL-17, IL-21, IL-22 they stimulate the extremely large number of immune and non-immune cells (T cells, neutrophils, macrophages, NK cells, B cells, epithelial and endothelial cells), resulting in progressive chronic inflammation, enhancement of phagocytosis and antibody synthesis, maturation of myeloid cells, autoimmune response.
- Another T helper subset of follicular T helper cells TFH arises from Th0 by the contact with antigen-presenting B cells in the follicles of lymph nodes. When activated, TFH stimulates the transformation of follicular B lymphocytes into long-living antibody-secreting plasma cells and memory B cells.
Regulatory T cells
- Regulatory T cells or Treg are differentiated as natural immune suppressor cells. Molecular markers of this cell type are CD4 and CD25 that are co-expressed together upon cell membranes.
- Also, natural regulatory T cells contain the active form of specific transcriptional factor Foxp3.
- After the recognition of Ags presented by dendritic cells, Treg expresses co-stimulatory inhibitory molecule CD-152 resulting in suppression of the activity of antigen-presenting cells.
- In addition, they produce large amounts of inhibitory cytokines TGF-beta and IL-10 that restrain the proliferation of various subsets of immune cells.
- Overall, T helpers comprise up to 40-50% of lymphocytes.
T cytotoxic cells
- T cytotoxic cells (or Tcs) pertain to the T cell subset bearing CD8 marker.
- They recognize the antigen in complex with HLA-I class molecules presented on the membranes of infected cells or cancer cells.
- Therefore, cytotoxic T cells eliminate intracellular pathogens (viruses or bacteria) and participate in host immune surveillance by killing of malignant cells.
- Co-stimulatory CD8 molecule binds to HLA-I class antigens supporting antigen recognition by cytotoxic cells.
- Activated (CD8+) T cells (T killers) bind to the antigens on the membranes of affected host cells and activate apoptosis or programmed death of target cells.
- To aim this, Tcs produce cytotoxic proteins perforin, granzymes, and granulysin. Perforin acts as pore-forming toxin allowing granzymes to enter the cell and stimulate apoptosis via activation of caspases.
- In addition, Tcs stimulate apoptosis by elevated expression of FasL that binds to apoptosis receptor CD95 Fas/Apo upon the membranes of target cells.
Memory T cells are long-living subpopulations of CD4+ and CD8+ cells arisen from activated T cells bearing antigen-specific TCR. Their lifespan lasts for more than 20 years. In case of the next antigenic challenge, they serve as progenitors for the burst emergence of antigen-specific T cell clones.
T Cell Receptor
- T cell receptors (TCRs) belong to the superfamily of immunoglobulin molecules with basic domain structure.
- TCR is expressed on T cell membranes. It is the heterodimeric molecule composed of alpha– and beta–chains (with molecular weight about 40-50 kDa each) or more rarely of γ/δ-chains. T cells bearing γδ TCR version (about 1-5% of total lymphocyte count) take part in local immune reactions within the mucous tissues.
- TCR is bound tightly to the CD3 molecular complex on the T cell membrane.
- Every chain of TCR is composed of constant and variable globular domains.
- The variable domain contains the antigen-binding site of TCR. It recognizes the processed antigen only in the complex with HLA-I or II class molecules (“double recognition” or “HLA restriction” phenomenon).
- There is a large quantity of V, D, and J gene segments (totally more than 150) that code for the variable portions of TCR chains.
- Each individual sequence of TCR binding site results from the random recombination (rearrangement) of certain genetic V, D, and J segments. This process generates the prominent variability of T cell specificities.