MHC molecules have a Kd of 10-6 M. This does not change during an immune response. In contrast, the Ag binding site of Abs has a Kd of around 10-7 M, which may increase during the course of the immune response to 10-11 M by affinity maturation. The mechanism of this is a process of somatic mutation. In addition, B-cells have the means to change the avidity of their antibodies by class-swiching. T-cells lack the genetic mechanisms for somatic mutation of their TCR to increase affinity. However, Slifka and Whitton found that functional avidity of the T-cell response increased from.
Invariant MHC-tetramer staining indicated that the affinity of the TCR had not increased3. As a mechanism for this avidity maturation of TCRs, topological changes of the composition of T-cell rafts has been put forward4. Signalling Binding is not enough for specific antigen recognition. Crucially, recognition involves signal transduction across the plasma membrane. It is not clear whether the MHC transduces a signal back to the antigen-presenting cell and analysis of the intracellular domain has not yielded any evidence for a role in signalling.
However, the type of MHC carries information concerning the compartment from where the antigen was sampled. Binding of the TCR to a peptide/MHC complex on the other hand results in transduction of a signal to the T-cell. Several lines of evidence support this idea and indicate how this might be achieved. The TCR forms a complex with trimeric CD3. Anti-CD3 antibodies may activate T-Cells in a similar manner to binding of the MHC/peptide complex to the TCR, if the T-cell line does not depend on co-stimulation.
In addition, chimeric molecules have been engineered where the extracellular and transmembrane domains of the IL-2 Receptor were engineered on the cytoplasmic domain of CD3. Binding of IL-2 to these chimeric receptors had identical effects to MHC/peptide binding. Similarly, membrane-bound antibodies are form a complex with Ig? and Ig. These transmembrane proteins signal specific antigen recognition when the BCR is crosslinked by the binding of its antigen. Secreted antibodies on the other hand can activate immune cells with their Fc receptors.
In addition, they may activate the classical pathway (in the case of IgA also the alternative pathway) of complement, which serves to amplify the danger signal. Conclusion MHC, TCR and Ab molecules achieve specific Ag-recognition very differently. Importantly, the knowledge about these different mechanisms has helped us devise rational therapy and improve differential diagnosis. For instance, altered peptide ligands have been engineered to antagonize the function of T cells in autoimmune disease.
This is a direct consequence of the model of specific antigen recognition by TCR outlined above, and has been achieved by changing the peptide residues of the peptide that make contact with the TCR. In the case of pemphigus vulgaris, the model of specific Ag recognition by the MHC has been able to explain the pathogenesis of an autoimmune disease. In HLA-DRB1*0402, the P4 pocket is formed by negatively charged amino acids. These can make a strong association with certain peptides processed from desmoglein, whose P4 residues carry a positive charge. This strong association leads to a T-cell response and autoimmune disease.
In contrast, the wild-type HLA-DRB1 molecules do not have negatively charged residues at the P4 pocket. Screening for this particular mutation in the class II MHC has helped differential diagnosis and might lead to the ability to prevent the disease before it has become clinically apparent. T Konrad Rajab – 1465 words 1 Arstila et al. “A direct estimate of the human alpha beta T cell receptor diversity”.
Science 1999; 286:958 2 von Andrian et. al. “T cell Function and Migration” N. Engl. J. Med. 343: 1020 3 Silfka MK & Whitton JL, Nature Immunol. 2: 711 (2001) 4 Margulies DH, Nature Immunol. 2 : 669 (2001)