T cells are divided into two major groups: CD4+ T-helper and CD8+ T-cytotoxic cells. Th cells are further subdivided into type 1 and type 2, also known as Th1 and Th2. The differentiation of T cells into CD4 vs. CD8 occurs during their development in the thymus. The differentiation of Th cells into Th1 and Th2 occurs only after these cells have been activated during an immune response, in the peripheral lymphoid system.
T CELL DEVELOPMENT
T cell differentiation into Th1 & Th2
cells after activation is not considered as part of T cell Development, but part of the
normal immune response.
T cell development occurs in the thymus (clinical, DiGeorge, nude mice). T cell precursors however arrive to the thymus from the Bone Marrow. The stages of T cell development are identified by the expression of specific cell surface markers, such as TCR (T Cell Receptor), CD3 (which serves as the signal transduction component of TCR), and CD4/CD8. Direct cell to cell interaction between these cells and thymic cells induces their proliferation and also differentiation. Pre-T cells do not express any of the above mentioned T cell markers. At this stage they are referred to as Double Negative cells (because they are CD4 and CD8 negative). At this point the alpha-chain of TCR undergoes rearrangement. The successful rearrangement of this chain serves as a signal for these cells to undergo further proliferation. During this time, both CD4 and CD8 start to be expressed, thus these cells are referred to as Double Positive cells. It is only at this point that the beta-chain of the TCR undergoes rearrangement. At this stage these cells undergo the processes of Positive and Negative selection.
Positive selection:
Since TCR's recognize antigen only in the context of MHC's, T cells must be tuned to
recognize host MHC first. During positive selection Double-Positive T cells that can
recognize self MHC's are selected for proliferation, and those T cells that do not
recognize self MHC die via Apoptosis. Positive selection also assures that the right TCR
selection will go with the appropriate CD4 or CD8. For example, TCR's specific for MHC II
need to retain CD4, and lose CD8. If the reverse occurs, they will die via apoptosis. The
same is true for the T cells that are specific for MHC I, which need to retain CD8, and
lose CD4 (Reminder: CD4+ Th cells recognize MHCII,
and CD8+ Tc cells recognize MHC I)
Negative
selection:
At this point, those T cells that are strongly activated by self MHC plus self peptides
need to be eliminated in the thymus. If they escape this elimination, they may
subsequently react against self antigens, and cause Autoimmune disease.
In summary, Positive selection selects for those T cells that react with MHC: self
antigen. Negative selection eliminates those that react strongly with MHC: self antigen.
Thus, successful T cell differentiation selects for MHC restricted TCR's with low affinity
for self antigens. Cells that
fall outside this range, primarily die via apoptosis. The rationale here is that a T cell
that binds weakly to self MHC/self Antigen will not be activated but will be activated by
a stronger binding to self MHC/ foreign Antigen complex..
Unlike B cells, T cells do not recognize antigens directly. They "see" antigen as peptides ONLY in association with host surface MHC (Major histocomptability) molecules. Since MHC molecules can only bind peptide molecules of 7-15 amino acids long, T cells only recognize their specific antigen in the form of small peptides. The antigen presenting cells such as macrophages and B-cells take up antigen and partially degrade it into peptides which then occupy the antigen-presenting groove in MHC-I and MHC-II molecules.
Note that T cells canNOT recognize "whole" intact antigens nor non-proteinaceous antigens such as carbohydrates.
There are two classes
of MHC molecule
1) MHC class I , which primarily present intracellular antigens.
2) MHC class II , which primarily present extracellular antigens.
CD8+ Tc cells can only
recognize antigen in association with MHC I. The role of the CD8 molecule would be to bind
MHC I and thus strengthen this association. Without interaction with CD8, Tc cells will
not be activated.
CD4+ Th cells can only bind antigen in association with MHC II. This is because CD4 only
binds to MHC II. Without interaction with CD4, Th cells will not be activated.
Consequently, CD8+ Tc cells are activated by intracellular (e.g. viral) antigens, and CD4+ Th cells are activated by extracellular (e.g. bacterial) antigens. Hence, activated Tc cells kill the cells to which they bind, i.e. infected tissue cells. On the other hand, Th cells should not kill the cell that activates it, i.e. Antigen Presenting Cells, because these latter cells are not infected, but are just presenting an exogenous antigen.