The field of immunology has been grounded in basic biology since its inception, with myriad applications to human disease. Development of both preventive and therapeutic vaccines as treatments for human infectious diseases dates to the time of Pasteur's efforts in the nineteenth century (Debre and Forster, 1998). Since then, harnessing immunity through precise knowledge of molecular and cellular mechanisms was perceived as important in medical science.
Adaptive immunity is the most sophisticated and effective system to combat and rid infectious pathogens (Murphy et al., 2007). Adaptive immunity endows jawed vertebrates, including mammals, with precursors of T (thymus-derived), and B (bone marrow-derived) lymphocytes able to generate a repertoire of clonotypic antigen receptors (TCR and BCR) of immense diversity from somatic rearrangements of variable gene segments (VDJ recombination). Spatio-temporally controlled differentiation and selection processes of those cells shape two complementary “arms” of the immune system, offering protection with exquisite specificity, sensitivity, and long-term memory.
Key discoveries during the last quarter of the twentieth century began to unravel the cellular and molecular nature of adaptive immunity. In the 1960s, T and B lymphocytes were identified and their interactions shown to be essential for antibody production. The basic paradigm of immunoglobulin (Ig) gene rearrangements that generate antibody diversity was revealed in 1976 (Tonegawa, 1993). The “dual” specificity of T cells for foreign peptide and self-MHC inferred by functional studies was discovered and clearly noted to be distinct from the “single” specificity of antibody recognition of foreign proteins (Zinkernagel, 1997). This realization then led to an intense effort to understand the molecular puzzle represented by the self versus non-self recognition and the receptor and ancillary molecules on T cells responsible for this unusual recognition.
Initial studies suggesting the existence of an “I-J-specific” suppressor factor secreted by T cells and TCR specificity achieved through Ig genes were refuted. Rather, the discovery of how to expand T cells in vitro, via IL-2 dependent T cell cloning (Baker et al., 1979), in conjunction with monoclonal antibody (Milstein, 1993), and flow cytometry screening (Julius et al., 1972) technologies together with in vitro functional analyses were decisive in molecular identification for the long sought-after TCR. The key breakthroughs came in the early 1980s with the identification in human of a clonotypic disulfide-linked heterodimer, the αβ Ti, which together with CD3 molecules, were essential for antigen/MHC recognition and cellular activation (Reinherz et al., 1982; Acuto et al., 1983a; Meuer et al., 1983a,b). Biochemical evidence showed that, similar to Ig molecules, both Ti α and β chains possessed variable and constant regions (Acuto et al., 1983a,b). A comparable αβ Ti was soon identified also in the mouse in 1983, with similar cognate immune recognition features (Haskins et al., 1983; Kappler et al., 1983). Those murine studies supported an earlier suggestion that a tumor-specific marker on mouse T-lymphoma cells might be TCR-related (Allison et al., 1982). Within 2 years, cDNAs for TCR αβ subunits were obtained by several groups including Davis and Mak with the bona-fide identification established by the Ti αβ protein sequence (Acuto et al., 1984; Hedrick et al., 1984a,b; Yanagi et al., 1984). Collectively, these results confirmed the clonotypic nature of the Ti αβ first identified biochemically. These studies showed that TCR combinatorial diversity was generated by the same type of site-specific gene recombination mechanisms as with Ig genes, but without somatic hypermutation and led to identification of a second type of TCR, the γδ TCR (reviewed in Tonegawa, 1993).
CD4 and CD8 co-receptors identified during the same period, were soon recognized as ancillary structures that optimize TCR recognition and T cell activation via interaction with monomorphic segments of MHC class II and I molecules, respectively (Meuer et al., 1982). A few years later, the “dual recognition” puzzle was solved when it was shown that MHC class I and class II proteins bound foreign and self-peptides derived from degradation of intracellular or exogenous proteins and that such complexes could be recognized by the TCR (reviewed in Unanue, 2006). Structures of peptides complexed with MHC molecules then followed (Bjorkman et al., 1987; Jardetzky et al., 1994).