T-cell clones and T-cell receptors

The T-cell receptor for antigen (TCR) has finally been identified and characterized biochemically, and considerable information has been obtained about the organization of the genes that code for the TCR peptides. Why did this structure remain elusive for so long? It had been clear for many years that T lymphocytes play a central role in immune reactions, carrying out important effector and regulatory functions. On the basis of the immunological specificity of T-lymphocytes responses, it was clear that these cells have specific receptors which enable them to recognize particular antigens. It proved difficult, however, to identify these structures. This problem was related in large part to the complexity of the requirements for T-cell activation. Antigen molecules appear not to react directly with responding T cells; rather, antigen must be processed into suitable fragments which are then presented by an appropriate accessory cell (234). Direct binding of antigen by T cells can be demonstrated only rarely (209). In addition, the antigen-presenting cell (APC) must express the appropriate cell surface glycoproteins encoded in the major histocompatibility complex (MHC) (257). For most helper T lymphocytes (HTLs), these are class II antigens of the MHC; for most cytolytic T lymphocytes (CTL), these are class I antigens of the MHC. The molecular basis for this MHC-restricted antigen recognition by T cells is not known. It is tempting to assume that it can be explained by the association of the nominal antigen with MHC molecules on the cell surface to produce a complex that is recognized by the T cell (202). Regardless of the mechanism, the phenomenon of MHC restriction is a key feature of T-cell responses. This restriction also indicates that T-cell activation involves more than a simple interaction of nominal antigen with the antigen receptor. It should also be noted that the restriction pattern for antigen recognition appears to be acquired during T-cell development in the thymus (58). Two other factors have complicated the analysis of antigen recognition by T cells. First, T-cell responses are defined almost entirely in operational terms; an interaction between antigen and T lymphocytes can be recognized only by the effects that it produces. Usually, proliferation or secretion of lymphokines in response to a specific antigenic challenge or cytolysis of target cells bearing specific antigens is measured, although recently biochemial events have been used as earlier indicators of T-cell activation. Second, as noted above, more than one cell type is involved in T-cell responses. Often, bulk populations. of cells from lymphoid tissues of immunized animals are studied; these cell preparations include macrophages and distinct Tand B-lymphocyte subsets as well as other cells. In such populations, cells present in very low numbers can produce responses that can be measured accurately. However, the essential biochemical processes associated with such responses cannot be analyzed accurately because the proportion of responding cells is small. The same sort of unsatisfactory situation formerly existed with respect to antibodies. Until it was possible to characterize antibodies chemically as immunoglobulins, an antibody could be defined only in terms of its reactivity' with a given antigen, and an antigen was defined in terms of its reactivity with an antiserum. The development of homogeneous sources of immunoglobutin and of immunoglobulinproducing cells made it possible to define first the chemical and later the genetic basis for immunoglobulin structure. Myeloma proteins and myeloma tumor cells and, later, hybridoma antibodies and antibody-producing hybridoma cells provided the materials that were necessary for deter-