T cell Biology
T cell Development
T cells are distinguished by having CD3 on their surface. They are produced by lymphoid cells in the bone marrow which then migrate to the thymus in early fetal life. As each T cell matures in the thymus it develops a unique T cell receptor (TCR) type through a lymphocyte specific process of gene recombination, which from a large number of potential segments, randomly rearranges and recombines them into a final sequence to create a complete TCR, replicated many times (average 20,000) on its surface.
The function of the TCR is to bind to antigens presented by HLA molecules. In most instances the antigen is a fragment of a virus or bacterial coat but in transplant it is the donor HLA molecule. The random nature of TCR production allows TCRs to be produced that are able to act against self HLA. T cells with strongly self reacting TCRs undergo negative selection and are eliminated by thymic dendritic cells (derived from bone marrow).
The TCR binds to the antigen and HLA complex. The TCR thus has to have some affinity to self HLA, otherwise it would not be able to respond. Positive selection therefore occurs with the cortical thymic epithelial cells (TEC) allowing those T cells with a TCR weak affinity for self HLA molecules to survive and eliminating those with insufficient affinity. T cells undergo further differentiation in the thymus. Those expressing CD4+ on their surface (naïve T cells) and those expressing CD8+ (cytotoxic T cells). In addition a small proportion become regulatory T cells (Treg).
Eventually 3-5% survive this selection process and in the human up to 100 million T cells, each with a unique TCR, are released into the periphery. They are long lasting (years/decades) and each is able to multiply and produce clones. Thymic output of new T cells decreases over time because of thymic involution, making peripheral division of existing cells the main source of naive T cells from early adulthood onwards in humans.
Note: HLA (human leukocyte antigen) in humans is known in other species as the MHC (major histocompatibility complex)
T cell Activation
Naiive T cell activation involves the integration of three distinct signals delivered in sequence: antigen recognition; costimulation; cytokine-mediated differentiation and expansion. Antigen presenting cells (APCs) for example B lymphocytes, dendritic cells, macrophages, monocytes, Langerhans cells, endothelial cells, digest pathogens or donor tissue (antigen processing), and the resulting fragments are displayed on the cell surface by HLA glycoproteins (antigen presentation). APCs vary in whether they present the antigen on HLA class I or II glycoproteins. Class I presentation leads to activated CD8+ (cytotoxic T cells) whilst Class II glycoproteins activate CD4+. Dendritic cells can present antigens with either class I or II glycoproteins, while most present using Class II glycoproteins. Regardless of class type the HLA/antigen complex then binds to the TCR - Signal 1 (Figure 1).
Figure 1. Philip Halloran. N Engl J Med 2004;351:2715-29.
The TCR is unable to initiate T cell activation by itself and requires CD3 with which it is closely associated (TCR/CD3 complex), to transduce Signal 1 into the T cell. Antigen presenting cells (APC) provide Signal 2 (co-stimulation) , when CD80 and CD86 on the surface of the APC engage CD28 on T cells. These 2 signals are then transduced to the T cell nucleus by several pathways, including the calcineurin path. The nucleus then signals the production of transcription factors that trigger the expression of cytokines, that in turn, interact with the APC and activate the “target of rapamycin” (mTOR) pathway to provide Signal 3, triggering cell proliferation.
The complexity of the co-stimulation can be seen in Figure 2 and it determines the type of effector T helper cell develops into as shown in Figure 3
The effector functions of an activated naïve CD4+ T cells (now called T helper cells) and CD8+ are different. CD4+ T helper cells have a wider range of effector functions, all of which involve the targeted delivery of cytokines. Here are examples of the Interleukin 2 (IL-2) family of cytokines. Three distinct types of CD4+ T Cells have been distinguished: TH1 cells that secrete IFN-y, which mediate defence against intracellular microbes; TH2 cells that secrete IL-4 and IL-5, which favour IgE and eosinophil/mast T cell-mediated immune reactions against helminths; and TH17 cells, which promote inflammation and mediated defence against extracellular fungi and bacteria.
CD8+ T Cells have a cytotoxic function that enables them to kill cells infected with viruses and cancer cells. Regardless of CD type, activation of T cells to effector cells, results in proliferation, differentiation, and migration to diverse sites to promote pathogen clearance. Activated effector cells are short-lived, although a proportion survive as memory T cells.