Mohammad Ismail  ( Biomedical Division, National Institute of Biotechnology & Genetic Engineering, Postgraduate Medical Institute, Lahore. )
Sajid A. Qureshi  ( Department of Pathology, Postgraduate Medical Institute, Lahore. )

The immune system is crucially involved in a number of diseascs including microbial infections, aller­gies, cancer, rheumatism, autoimmunity and degenera­tive disorders of ageing. While the T- lymphocytes play a key role in the body’s immune defence mechanism, they also act to reject grafted or transplanted tissues.
The T-cells comprise only about half the population of lymphocytes; the other half, the B-lymphocytes being involved in secretion of antibody (immunoglobulin) molecules which also act as receptors when still bound to the B-cell surface. Since T- cells are antigen-specific, they must exhibit receptor molecules on their surface analogous to the membrane-bound immunoglobulins on
the B-cells. The ‘f-cell receptor (TCR) is membrane-bound and, unlike immunoglobulins, is not secreted from the cell¹. Again unlike immunoglobulins, the TCRs do not bind soluble antigens like bacterial toxins².
The structure of the TCRs is now rapidly coming into focus and the structural clarification is increasing our knowledge of the interactions of T-cells with other elements of the immune system.

The T-lymphocytes can be distinguished from the remaining haemopoietic cells by a marker called the CD3 complex, Lssociated with the TCRs for antigen³, which can be identified by a monoclonal antibody OKT3^4,5.
The CD3 + T-cclls can be further divided into sub-populations according to their expression of CD4⁶ and CD8 proteins. About two-thirds of the CD3 + cells express CD4 but not CD8 and one third CD8 but not CD4 proteins. They are referred to as CD4+ (CD4+ 8) and CD8+ (CD4- 8+), respectively. Avery small proportion of CD3 + cells, however, neither express CD4 nor CD8 and may be referred to as CD4+ 8⁷.
A unique and important property of the TCRs is that they only recognize the antigens (peptides) which are associated with the major histocompatibility complex (MHC) molecules on the cell surface⁸. MHC molecules are proteins encoded by the genes of the MHC chromosomal region⁹. The two classes ofMHC molecules involved are the class I MHC proteins expressed on most nucleated cells and class II MHC proteins which are expressed only on B- lymphocytes, macrophages, dendritic T-cclls and epithelial cells of the thymus. The class I proteins usually associate with peptides present in the cytosol including degraded products of viral proteins in virally infected cells¹⁰ which are transported to the cell surface by an unknown mechanism⁷. The class II MHC proteins bind peptides derived from external proteins which are endocytosed by inacrophages, dendritic T­cells or B-cells and are cleaved in lysosomes. The CD4+ cells bind peptides associated with class II MHC molecule while the CD8+ cells bind peptides associated with class I MHC molecule⁷. Antigen recognition by T­cells is therefore considered MlIC-restricted.
The 1’-cells produce lymphokines^11-13 and also express receptors which bind these lymphokines and hence regulate their growth and differentiation⁷. The best characterized of these receptors is the IL-2 (inter­leukin-2) receptor which is expressed by both activated CD4+ and CD8+ cells⁷. The CD3+4\'8\' cells can also be induced to produce IL-2 and become cytolytic¹⁴ but their antigen-specificity is not known.

Based on their structural components, TCRs can exist as heterodimers (with 2 non-identical chains) or homodimers (with 2 identical chains). Two hetcrodimer forms and one homodimer form have been detected. The two heterodimeric forms either consist of an alpha chain and a beta chain (alpha/beta TCR)” or a gamma chain and a delta chain (gamma/delta TCR)^16-18 of proteins. A homodimer TCR, the gamma/gamma TCR has also been described¹⁹.
The alpha/beta TCR recognizes protein fragments presented by class I or class II MUC-encoded molecules but the antigens recognized by the gamma/delta TCR are still being defined¹⁵ and the physiologic significance of gamma/delta TCRs remains unclear^20,21.
In man, gamma/delta TCRS comprise majority of the dendritic epidermal T-cells and 1-10 per cent of peripheral blood T- cells’ evenly distributed throughout the lymphoid organs and skin- and gut- associated lymphoid tissue, with no discernible local preference^18,22,23. Some local preference in certain species and the limited TCR diversity of gamma/delta TCRs lead to the hypothesis that gamma/delta TCRs are a phylogenetically very old surveillance system to monitor cell integrity and to destroy transformed or infected cells²⁴.
The alpha/beta TCR binds to both the peptide as well as the polymorphic residues of MHC molecules. The antigen recognition by the alpha/beta TCR is facilitated by the CD4 and CD8 co-receptors expressed in a mutually exclusive fashion on mature T cells²⁵. The CD4 and CD8 co-receptors bind to the nonpolymorphic residues of the class II and class I MHC molecules, respectively¹. Unlike the alpha/beta TCR, both the gamma/delta TCR and the gamma/gamma TCR arc not MHC-restricted²⁶.

The TCRs, like the MHC molecule, consist of two disulfide linked variable glycoproteins27,28. In the alpha/beta TCR, the alpha glycoprotein has a molecular weight of 43-49 kd while the beta glycoprotein is 38-42 kd, both of which are heterogenously charged glycoproteins^27,28. The TCR alpha chain contains nitrogen-linked oligosaccharides of the complex type and TCR beta chain comprises of both high mannose and co inpiex nitrogen-linked glycan side chains^26,27.
The organization of the TCR proteins is very similar to the antigen binding fragment (Fab segment) of immunoglobulins^1,26,29. As in the immunoglobulin molecule, all TCR proteins have a variable (V) region and a constant (C) region which are linked by a short joining segment 0) while the TCR beta and TCR delta chains also have a diversity (D) segment’.
The TCR proteins also have a transmembrane region and a short cytoplasmic tail of 5-12 aminoacids extending into the cytoplasm of the T-cell. The two cysteine residues in each of the V and C regions indicate an interchain disulfide loop in each region. The TCR alpha chain and TCR beta chain have cysteine residues proximal to the transmembranc region that form an inter-chain disulfide bond²⁶. The gamma TCR chain which is a 55 kd protein product and the delta TCR which is a 40 kd protein¹⁷ arc also covalently linked to form a gamma/delta TCR heterodimer or a gamma/gamma TCR homodimer^16,19,30.
The chromosome location of the CD3 gene is at 11q23, that of alpha TCR at 14q1 1, beta TCR at 7q32-35 and gamma TCR at 7pl5 while the delta TCR gene is still under study²⁶.The TCR genes are first rearranged and expressed in the thymus during the T-cell differentiation. The TCR beta, gamma and delta genes are rearranged and transcribed first, followed by the alpha chain gene¹.
The appearance of gamma/delta heterodimers precedes the alpha/beta TCR expression by one or two days in fetal ontogeny, as studied in the mouse. It has been suggested that only those cells that cannot produce a gamma/delta heterodimer proceed to alpha and beta expression. Alternatively, these two different types of T cells represent separate ëompartments and express their respective TCR chains independently¹.

The structural clarification of the TCR has brought about afar better under standing of the complex physiology of the T-cells, and the medically important properties of the cell mediated limb of immunological response. This revolution­ary advance in knowledge is expected to aid in improving the management of various diseases, especially viral infections, allergies, autoimmunity and cancer.

1. Davis, M. and Bjorkman, P.J. T-cell antigen receptor genes and T-cell recognition. Nature, 1988; 334:395.
2. Zinkernagol, R.M. and Doherty, P.C MHC-restricted cytotoxic T celia; studies on the biological role of polymorphic major transplantation antigen determining T-cell restriction- specificity, function and responsiveness. Adv. Immunol., 1979; 27:51.
3. Brenner, MB., Trowbridgc, I.S. and Strominger, J.L Cross- linking of human T cell receptor proteins; association between the T cell idiotypc beta aubunit and the T3 glycoprotcin heavy subunit. Cell, 1985; 40:183.
4. Leo, 0., Foo, 84., Sachs, D.H., Samelson, LB. and Bluestone, J.A. Identilication of a monoclonsi antibody specific for a murine T3 polypcptide. Proc. Nat. Acad. Sci. USA., 1987; 84:1374.
5. van Agthoven, A., Terhorat, C., Reinherz, E. and Schlossman, S. Characterization of T cell surface glycoproteine TI and T3 pretent on all human peripheral T lymphocytes and functionally mature thymocytca. tEar. 3. Immunol., 1981; tt:t8.
6. Williams, A.F., Gslfrc, F.G. and Milstein, C. Analysis of cell surface by xenogenic mycloms hybrid antibodies: Differentiation antigen of rat lymphocytes. Cell, 1977; 12:663.
7. von Boehmer, H. The developmental biology ofT-lymphocytes. Annu. Rev,lmmunol., 1988; 6:309-326.
8. Schwartz, RH. 1-lymphocyte recognition of antigen in association with gene products of the major histocompatibility complex. Anou. Rev. lmmuool., 198.5: 3:237.
9. Steinmetz, M. and Hood, L Genes ofthcmajorhistocompatibility complexin mousesnd man. Science, 1983; 222:727.
10. Townsend, ARM., Rothbard, 3., Gotch, F,M., Bahadur, C., Wraith, D. and McMichal, A.J. Theepitopes ofinfluenzs nucleoprotein recognized by cytotoxic T-lymphocytes can be defined with short synthetic peptides. Cell, 1986; 44:959.
11. Morgan, D.A., Ruscetti, F. W. and Gallo, it Selective in vitro growth of T lymphocytes from normal human bone marrows. Science, 1976; 193:1007.
12. Smith, K A.T-cell growth factor. Immunol. Rev., 1980; 51:337.
13. Howard, 84., Farrar, 3., Hilfiker, 84., Johnson, B., Takatsu, K., Hamsoka, T. and Paul, WE. Identification of a T cell-derived B cell growth factor distinct from interteukin 2.J. Exp. Med., 1982; 155:914.
14. Ferrini, S., Bottino, C., Biassoni, It, Poggi, A., Sekaty, R.P., Moretta, Land Moretta, A. Characterization of CD3 +, CD4, CD 8 clones expressing the putative T cell receptor gamma gene producc Analysis of the activation pathways leading to interlcukin 2 production and triggering of the hytic machinery. 3. Exp. Med., 1987; 166:277.
15. von Boehmcr, H. and Kisielow, P. SeIf-Nonself discrimination hyT cells. Science, 1990; 248:1369.
16. Borst, 3., van de Griend, R.J., van Oostveen, 3W., Ang, S.L., Melief, C.J., Seidman, 3G. and Boihuis, R.L AT-cell receptor gamms/CD3 complex found on cloned functional lymphocytes. Nature, 1987; 325:683.
17. Brenner, MB., McLean,J., Scheft, H., Riberdy, J., Ang. S.L, Seidman, J.G., Devlin, P., and Krsngel, M.5. ‘Pro forms of theT- cell reccptorgamms protein found on peripheral blood cytotoxicT lymphocytes. Nature, 1987; 325:689.
18. Raulet, D.H. The ttructure, function, and molecular genetics of the gamma/delta TcelI receptor. Annu. Rev. Immunol., 1989; 7:175.
19. Atarcon, B., De Vries, 3., Pettey, C., Boylston, A., Ysset, H., Terhorst, C. and Spits, H. The 1-cell receptor gamma chain CD3 complex; implication in the cystotoxicactivity of a CD3+, CD4’, CD8’ human natural killer clone. Proc. Nstl. Acad. Sci. USA., 1987; 84:3861.
20. Strominger, J.L The gamma delta T cell receptor and class lb MHC-related proteins; enigmatic molecules of immune recognition. Cell, 1989; 57:895.
21. Bluestone,J.A. and Matis, L.A. TCRgamma delta cells; minor redundsntT cell subset or specialized immune system compartment 23. Immunol., 1989; 142:1785.
22. Groh, V., Porcelli, S., Fabbi, M., et al. Human lymphocytes bearing T cell receptor gamma/delta are phenotypicattydiversc and eventydistributed throughout the lymphoid system. J. Exp. Mcd., 1989; 169:1277.
23. Bury, R.P., Chen, C.H. and Cooper, M.D. Tissue localization and COB accessory molecule expression ofTgamma delta cells in humans. 3. Immunol., 1989; 142:3045.
24. Janeway. C.A., Jones, B.J. and Hayday, A. Specificity and function of T cells bearing gamma delta receptors. Immunol. Today, 1988; 9:73.
25. Dembic, 7_, Haaa, W., Zamoyska, R., Panics, 3., Stcinmetz, M. and von Boehmer, H. Transfection of the CD8gene enhances T-cell recognition. Nature, 1987; 326:510.
26. Clevers, H., Alarcon, B., Witeman, T. and Terhorat, C. The 1-cell receptor/CD3 complex; a dynamic protein ensemble. Annu. Rev. Immunol, 1988; 6:629.
27. Allison, J.P. and Lanier, L.LThe structure, function, and serologyof the T-cell antigen receptor complex. Annu. Rev. ImmunoL, 1987; 5:503.
28. Toyonaga, B. and Mak, T. W. Genes of the T-cell antigen receptor in normal and malignantTcells. Annu. Rev. Imrnunol., 1987; 5:585.
29. Danska, J.S.The T-cetl receptor; structure, molecular diversity and somatic localization. Curr. Opin. lmmunol., 1989; 2:81.
30. Moingeon, P., Jitaukawa, S., Faure, F., Troalen, F., Triebel, F.. Graziani, M., Forestier, F., Belles, D., Bohvon, C. and Hercend, T. A gamma-chain complex forms a functional receptor on cloned human lymphocytes with natural killer-tike activity. Nature, 1987; 325:723.