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MHC restriction
MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a given T cell can interact with both the self-MHC molecule and the foreign peptide that is bound to it, and will recognize the peptide antigen only when it is bound to a host body's own MHC molecule. As T cells are stimulated by peptide antigens only in the presence of self-MHC molecules, MHC restriction adds another dimension to the specificity of TCR so that an antigen is recognized only as peptide-MHC complexes.

MHC restriction in T cells occurs after its development in the thymus, specifically after positive selection. Only the thymocytes (developing T cells in the thymus) that are capable of binding, with an appropriate affinity, with the MHC molecules can receive a survival signal and go on to the next level of selection. MHC restriction is significant for T cells to function properly when it leaves the thymus because it allows T cell receptors to bind to MHC and detect cells that are infected by intracellular pathogens, viral proteins and bearing genetic defects. Two models explaining how restriction arose are the germline model and the selection model.

The germline model suggests that MHC restriction is a result of evolutionary pressure favoring T cell receptors that are capable of binding to MHC. The selection suggests that not all T cell receptors show MHC restriction, however only the T cell receptors with MHC restriction are expressed after thyme selection. In fact, both hypothesis are reflected in the determination of TCR restriction, such that both germline-encoded interactions between TCR and MHC and co-receptor interactions with CD4 or CD8 to signal T cell maturation during selection.

Introduction to MHC Restriction
The αβ TCRs of T lymphocytes recognize linear peptide epitopes only if coupled with a MHC molecule. In other words, the antigenic ligands of TCRs are specific peptide-MHC complexes. MHC restriction is particularly important when primary lymphocytes are developing and differentiating in the thymus or bone marrow. It is at this stage that T cells die by apoptosis if they express high affinity for self-antigens presented by an MHC molecule or express too low affinity for self MHC.

T cell maturation involves two distinct developmental stages: positive selection and negative selection. Positive selection ensures that any cells with a high enough affinity for peptide bound MHC survive, while negative selection induces death in cells which bind MHC too strongly. Ultimately, the T cells differentiate and mature to express either CD4 and TcR or CD8 and TcR. At this point the T cells leave the primary lymphoid organ and enter the blood stream.

The interaction between TCRs and peptide-MHC complex is significant in maintaining the immune system against foreign antigens. MHC restriction allows TCRs to detect host cells that are infected by pathogens, contains non-self proteins and bears foreign DNA. However, MHC restriction is also responsible for chronic autoimmune diseases and hypersensitivity.

Structural Specificity
The peptide-MHC complex presents a surface that looks like an altered self to the TCR. The surface consisting of two α helices from the MHC and a bound peptide sequence is projected away from the host cell to the T cells, whose TCRs are projected away from the T cells towards the host cells. In contrast with T cell receptors which recognize linear peptide epitopes, B cell receptors recognize a variety of conformational epitopes (including peptide, carbohydrate, lipid and DNA) with specific three-dimensional structures.

Imposition of MHC Restriction
The imposition of MHC restriction on the highly variable TCR repertoire has caused heated debate. Two models have been proposed to explain the imposition of MHC restriction. The Germline model proposes that MHC restriction is hard-wired in the TCR Germline sequence due to co-evolution of TCR and MHC to interact with each other. The Selection model suggests that MHC restriction is not a hard-wired property in the Germline sequences of TCRs, but imposed on them by CD4 and CD8 co-receptors during positive selection. The relative importance of the two models are not yet determined.

Germline Model
The Germline hypothesis suggests that the ability to bind to MHC is intrinsic and encoded within the Germline DNA coding for TCRs. This is because of evolutionary pressure selects for TCRs that are capable of biding to MHC and selects against those that are not capable of binding to MHC. Since the emergence of TCR and MHC ~500 million years ago, there is opportunity for TCR and MHC to coevolve to recognize each other. Evolutionary pressure would lead to conserved amino acid sequences at regions of contact with MHCs on TCRs.

Evidence from X-ray crystallography shows comparable binding topologies between various TCR and MHC-peptide complexes. In addition to conserved interactions between TCR variable regions and specific MHCs supports the hypothesis that MHC restriction is related to the co-evolution of TCR and MHC to some extent. However it has also been shown that T cell selection in the thymus and periphery T cell repertoire is independent of germline TCR sequence, arguing against the hypothesis that MHC restriction is intrinsic to germline TCR sequences.

Selection Model
The selection hypothesis argues that instead of being an intrinsic property, MHC restriction is imposed during positive thymic selection after random TCRs are produced. According to this model, T cells in the form of double positive thymocytes are capable of recognizing a variety of peptide epitopes independent of MHC molecules before undergoing thymic selection. During thymic selection, only the T cells with affinity to MHC are signaled to survive after the CD4 or CD8 co-receptors bind to the MHC molecule. This is called positive selection.

During positive selection, co-receptors CD4 and CD8 initiate a signaling cascade following MHC binding. This involves the recruitment of Lck, a tyrosine kinase essential for T cell maturation that is associated with the cytoplasmic tail of the co-receptors. Selection model argues that Lck is directed to TCRs by co-receptors CD4 and CD8 when they recognize MHC molecules. Since TCRs only interact wtih Lck when they are binding to the MHC molecules that are binding to the co-receptors, T cells that can interact with MHCs bound to by the co-receptors can activate the Lck kinase and receive a survival signal.

Supporting this argument, genetically modified T cells without CD4 and CD8 co-receptors express MHC-independent TCRs. It follows that MHC restriction is imposed by CD4 and CD8 co-receptors during positive selection of T cell selection.

Reconciliation
A reconciliation of the two models was offered later on. Co-receptor and Germline predisposition to MHC binding both play significant roles in imposing MHC restriction. Since T cells with the ability to bind MHC are selected for during positive selection in the thymus, evolutionary pressure acts on the germline TCR sequence selecting for MHC binding TCRs. MHC restriction also requires for TCRs to bind with the same MHC molecules as the CD4 or CD8 co-receptor to deliver a maturation signal to double-positive thymocytes during T cell selection.