T-cells

T-cells are major players in the cell mediated response in adaptive immunity. T-cells recognize processed antigen in contrast to B cells which recognize native, non-processed antigen.

Types of T cells:

There are 2 main subpopulations of T cells; T helper (T_H) cells and T cytotoxic (T_C) cells. T cells which display a CD4 glycoprotein generally function as T_H and are class II restricted whereas T_C cells generally display a CD8 glycoprotein and are class I restricted. The ratio of T_H to T_C cells is generally 2:1.

There are also a subpopulation of T cells called regulatory T cells. Several subsets of regulatory T (Tr) cells with distinct phenotypes and distinct mechanisms of action have been identified. These include type 1 Tr cells (Tr1) cells which secrete high levels of IL-10 and low to moderate levels of transforming growth factor (TGF-B, type 3 T (Th3) cells, which primarily secrete TGF-beta, and CD4+CD25+ T cells, which inhibit immune responses through cell-cell contact.

In addition to the various CD4+ Tr populations, recent studies have identified CD8+ Tr cells, which secrete either IL-10 or TGF-beta.

T cells are also classified as naive, effector and memory T cells.

The T Cell Receptor (TCR):

T Cell Maturation:

The same types of cells (prethymic) can give rise to not only T cells but other types of cells like NK and DC cells. So committment to T cells actually occurs quite late in T cell maturation. T cell progenitors enter the outer cortex of the thymus and slowly proliferate. For about 3 weeks, the T cells progress through a series of stages that are marked by characteristic changes in their cell surface phenotype. Thymocytes early in development lack detectable CD4 and CD8 and are thus referred to as double-negative (DN) cells. RAG proteins are first expressed in CD4-CD8- double negative (DN) T cells, in which genes encoding T cell receptor β chains (Tcrb) are assembled. Early thymocyte precursors, which express neither coreceptor are selected to differentiate further if they have productive rearrangements at the TRB locus (also known as TCRβ).

Sucessful Tcrb recombination induces Tcrb allelic exclusion, clonal expansion, Rag downregulation and T cell development to the  double-positive (DP) stage, where both CD4 and CD8 coreceptors are expressed. Rag genes are reinduced in the DP stage of thymocyte development; at this stage, genes encoding T cell receptor α (Tcra) recombine and Rag expression persists until a TCR is expressed on the cell surface and the thymocyte is positively selected by TCR crosslinking. Random rearrangement of a series of gene segments encoding the cell's antigen receptor  results in enormous diversity of unique receptor specificities.

Positive Selection for T cells that recognize self-MHC molecules

The diversity is diminished later on by a mechanism involving positive and negative selection. Positive selection for thymocytes bearing receptors that are capable of binding self MHC molecules occurs in the cortical region of the thymus and involves interaction of immature thymocytes with cortical epithelial cells. The mechanism appears to involve just enough affinity for self MHC that such T cells are positively selected. For those cells which do not have the requisite affinity for self MHC, death through apoptosis occurs. As an example of positive selection, monoclonal antibody to either MHC class I or class II will result in the lack of CD8 and CD4 T cells respectively suggesting that these T cells need interaction with class I or class II to develop (although you will see double negative and double positive T cells since those were already developed before positive selection). During positive selection, the RAG proteins required for gene rearrangement continue to be expressed. Only those cells whose alpha-beta TCR heterodimer recognizes a self-MHC molecule are selected for survival. The process of positive section insures that T cell receptors can recognize antigen only in association with cell membrane proteins called major histocompatbility complex (MHC) molecules.

Negative Selection to eliminate T cells with high affinity for self-MhC

The population of MHC restricted thymocytes that survive positive selection comprises some cells with low affinity receptors for self-antigen presented by self-MHC molecules and other cells with high affinity receptors. The latter thymocytes undergo negative selection by an interaction with thymic stromal cells in the thymic medulla. This process insures self-tolerance. Experimental evidence for negative selection was shown by preparing male and female transgenic mice which carried TCR transgenes specific for an H-Y antigen (that is only expressed by males) plus a specific MHC molecule. In this experiment, both male and female mice would have the same MHC molecule but only the male mice would present the H-Y antigen. FACS analysis of thymocytes showed that mature CD8 T cells expressing the transgene were absent in the male mice but present in the female mice. The reason for this absence in male mice was the deletion of those thymoctyes which reacted with a self-antigen (the H-Y antigen in the male mice). This experiment showed that negative selection of thymocytes requires both self-antigen and self-MHC.

Another important process which occurs in the thymus is selection of either CD4 or CD8 positive cells from the double positive cell population. Double positive thymoctyes that interact with MHC class II proteins differentiate into CD4+CD8^- T helper cells, whereas those that interact with MHC class I become CD8 single positive cytotoxic T cells. Various models have been proposed for this selection and the exact mechanism is not currently known.