Molecular Analysis of Major Histocompatibility Complex (MHC) Molecule Recognition by the T Cell Receptor Alpha-Beta (α-β) Heterodimer
We have examined the molecular basis of MHC-restricted antigen recognition and alloreactivity by the T cell receptor (TCR) α-β heterodimer in murine T cell clones specific for the peptide antigen pigeon cytochrome c. The T cell proliferative response to this antigen has been extensively characterized with regard to the fine specificity of both antigen and MHC molecule recognition. All T cell clones derived from B10.A strain mice share specificity for an antigenic determinant on the COOH-terminal peptide in association’ with the self E α k :E β k Ia molecule. However, distinct clonotypes can be identified based upon differences in the fine specificity of both antigen and MHC recognition, or concomitant alloreactivity. Structure-function analysis of TCR gene expression was performed by cDNA cloning and sequencing of productively rearranged α and β TCR genes from T cell clones representative of each clonotype, and by Southern blot analysis of a series of T cell clones of defined specificity using V segment probes derived from the cDNA clones.
This analysis demonstrated definite correlations between sequence changes in particular regions of the TCR and functional specificity. A single Vα subfamily gene segment was predominantly expressed by all the B10.A T cell clones. In association with this Va gene, a limited set of Vβ genes were expressed, each correlating exactly with a unique response phenotype. A striking selection of both Jα and Jβ gene segments was also observed within each clonotype. Thus, Vα−Vβ combinatorial association, V-J combinatorial joining, and junctional diversity were shown to affect both antigen and MHC specificities of the cytochrome c-specific T cell clones. These represent the predominant mechanisms for the generation of diversity in the TCR repertoire.
In addition, the data revealed significant homologies between TCR that recognize Ia molecules as restriction elements in association with antigen and TCR that recognize the same Ia molecules as alloantigens. This suggests that MHC-restricted recognition and alloreactivity may simply reflect differences in the affinity of the interaction between the TCR and the MHC molecule.
KeywordsMajor Histocompatibility Complex Cell Clone Gene Segment Major Histocompatibility Complex Molecule Major Histocompatibility Complex Specificity
Unable to display preview. Download preview PDF.
- Heber-Katz, E., Schwartz, R. H., Matis, L. A., Hannum, C., Fairwell, T., Apella, E., 1982, Contribution of antigen-presenting cell major histocompatibility complex gene products to the specificity of antigen-induced T cell activation, J. Exp. Med., 155: 1086.PubMedCentralPubMedCrossRefGoogle Scholar
- Janeway, C.A., Jr., Lerner, E. A., Conrad, P. J., and Jones, B., 1982, The precision of self and non-self major histocompatibility complex encoded antigen recognition by cloned T cells, Behring Inst. Mitt. 70: 200.Google Scholar
- Katz, D. H., Hamaoka, T., and Benacerraf, B., 1973, Cell interactions between histoincompatible T and B lymphocytes. II. Failure of physiologic cooperative interactions between T and B lymphocytes from allogeneic donor strains in humoral response to hapten-protein conjugates, J. Exp. Med., 137: 1405.PubMedCentralPubMedCrossRefGoogle Scholar
- Kronenberg, M., Siu, G., Hood, L. E., and Shastri, N., The molecular genetics of the T cell antigen receptor and T cell antigen recognition, Ann. Rev. Immunol., 4: 529.Google Scholar
- Matis, L. A., Longo, D. L., Hedrick, S. M., Hannum, C., Margoliash, E., and Schwartz, R. H., 1983, Clonal analysis of the major histocompatibility complex restriction and the fine specificity of antigen recognition in the T cell proliferative response to cytochrome c, J. Immunol., 130: 1527.PubMedGoogle Scholar
- Matis, L. A., Sorger, S. B., McElligot, D. L., Fink, P. J., and Hedrick, S. M., 1987, The molecular basis of alloreactivity in antigen-specific, major histocompatibility complex restricted T cell clones, Cell, in press.Google Scholar
- Schwartz, R. H., The role of gene products of the major histocompatibility complex in T cell activation, in: “Fundamental Immunology,” W. E. Paul ed., Raven Press, New York (1984).Google Scholar
- Schwartz, R. H., Fox, B. S., Fraga, E., Chen, C., and Singh, B., 1985, The T lymphocyte response to cytochrome c. V. Determination of the minimal peptide size required for stimulation of T cell clones and assessment of the contribution of each residue beyond this size to antigenic potency, J. Immunol., 135: 2598.PubMedGoogle Scholar
- Winoto, A., Mjolsness, S., and Hood, L., 1985, Genomic organization of the genes encoding the mouse T cell receptor a chain: 18 J segments map over 60 kilobases of DNA, Nature, 316: 832.Google Scholar