Abstract: Human T cells respond strongly to mouse major histocompatibility complex (MHC) antigens. The response is directed predominantly to the polymorphic determinants of the MHC antigens and there is little or no response to the nonpolymorphic determinants or to non-MHC antigens. Human cytotoxic T lymphocytes (CTL) are generated specific for the mouse class I MHC antigens and the CTL effectors are blocked by anti-Leu-2a antisera. Human interleukin 2-producing T cells are generated specific for mouse class II antigens and their induction is blocked by anti-Leu-3a antisera. These and other considerations lead us to propose a model for the T cell receptor that provides an explanation for several of the features of T cell recognition. In this model, the recognition of the "class" (I or II) of MHC antigen is separate from the recognition of the polymorphic determinants. We suggest that the initial recognition of the conserved "class" determinants positions another domain of the receptor so that it can only engage with the part of the MHC molecule carrying the polymorphic determinants.

Abstract: The human beta 2-microglobulin (beta-2m)-associated human thymocyte differentiation antigens T6 and M241 were compared using biochemical techniques. T6 and M241 antigens reside on different molecules with apparent m.w. of 49,000 and 43,000, respectively. Here we show that both proteins have a protein backbone m.w. of 33,000. In addition, T6 and M241 have a large portion of their peptides in common. When we compared the protein backbone m.w. of T6 and M241 with the murine beta-2m-associated thymus leukemia (TL) antigens, we found a considerable difference in size, suggesting that T6 and M241 may not be human homologues of TL antigens and constitute a novel type of major histocompatibility (MHC) class I antigens.

Abstract: The high frequency of T lymphocytes recognizing allelic variants of major histocompatibility complex (MHC) l products has puzzled immunologists. More than 50%, and possibly all T cells, recognize products of foreign MHC genes (13). Further studies have indicated that T cells specific for complexes of conventional antigen and self-MHC products (4) also react with foreign MHC products (5-8). This has suggested that a high degree of homology between (a) complexes composed of an individual's own MHC products and antigen, and (b) foreign MHC gene products, is responsible for alloreactivity. Another possibility is that receptors for foreign MHC products are distinct from receptors for complexes formed by an individual's MHC and foreign proteins (9). The first demonstration that a single clone of T cells could recognize autologous class II MHC products associated with antigen as well as foreign class II MHC products, came from a reaction of a T cell clone with specificity for (a) ovalbumin plus syngeneic I-A k gene products and (b) I-A ~ gene products (10). A study of a series of BALB/c antiovalbumin clones also indicated that several reacted to foreign MHC products, and that these reactions were randomly distributed among the foreign MHC haplotypes tested (1 1). However, neither observation indicated whether or not "alloreactivity" included serum proteins in culture and, more importantly, whether this was due to binding by its receptor for conventional antigen and autologous MHC products. A direct approach to this requires a panel of cloned T cells with virtually identical specificities for a well-defined antigen and a particular self-MHC product. We shall term this physiologic reaction corecognition. If alloreactivity is, in fact, generated as a direct consequence of the gene product(s) responsible for corecognition, this panel should display a pronounced bias of reactivity to a particular foreign MHC product. We have tested this hypothesis and the results reported here indicate that a substantial number of clones with indistinguishable * Supported by grants AI 13600, CA 26695, and AI 12184 from the National Institutes of Health. J Abbreviations used in this paper: DME, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; 2-ME, 2-mercaptoethanol; MHC, major histocompatibility complex.

Abstract: The Ia or class II molecules in both mouse and man are the basis for the genetic control of the immune response. In addition to DR, other class II antigens have been described in man. We describe a new human Ia antigen K19, recognized by three monoclonal antibodies (HK-9, HK-19, and HK-20). This antigen has the general biochemical characteristics of an Ia antigen but is different from a DR antigen. Further, this antigen is found only on mature B lymphocytes and not on monocytes and activated T cells. Thus, this antigen may represent a new Ia-like molecule that is preferentially expressed on mature B cells.

Abstract: Generating an immune response to T-dependent antigens requires the cooperative interaction of APC, T helper cells, and B cells. T helper cells recognize antigen, not as soluble, native antigen, but as processed antigen in association with Ia molecules on the surface of an APC. Investigators from our laboratory demonstrated previously that some B lymphoma cell lines will present antigen to antigen-reactive T cells in an MHC-restricted fashion. These tumor lines are used in this study as a model system to examine the biochemical basis of antigen processing. Five different H-2d tumor cell lines, which differ in their ability to express Ia molecules and function as APC, are all shown to biochemically degrade sperm whale Mb in a similar manner. Intact Mb and four Mb fragments (4.3 to 12.5 Kd) were reproducibly recovered from each of these Mb-pulsed cell lines. This processed Mb is shown to be nonrandomly distributed in external and internal compartments, with the two smallest Mb fragments being enriched in the intracellular compartment. The Mb and Mb fragments can be completely removed from the surface of the APC by enzymatic proteolysis without quantitatively changing the ability of these cells to present Mb to Mb-reactive T cell lines. These results suggest that the processed Mb that is located intracellularly is the primary immunoreactive antigen for antigen presentation to T helper cells.

Abstract: It has been hypothesized that internalization and "processing" of the nominal antigen by antigen-presenting cells may be a mandatory event in antigen handling prior to cell surface presentation of the immunologically relevant moiety to T lymphocytes. In previous functional and immunochemical analyses of macrophage (M phi)-associated nominal antigen, we obtained data strongly suggesting that an immunologically relevant pool of antigen was detectable on the surface of M phi pulsed with a soluble protein antigen and then aged for 3-24 h. To provide further information about requisite events of M phi antigen handling, we have attempted to this study to determine the origin of the nominal antigen associated with the surface of the pulsed-aged cell using the terpolymer L-glutamic acid, L-lysine, L-tyrosine (GLT) as the antigen. The surface-bound GLT, after a 24-h culture, appeared to be derived from GLT initially surface-associated after the pulse. No evidence was obtained to support the notion that a significant quantity of GLT, initially internalized after the pulse exposure, was recompartmentalized to the cell surface. The turnover of cell-surface GLT resembled the turnover of M phi membrane proteins in general. These results, therefore, imply that the crucial events of M phi antigen handling of GLT may entirely be a cell surface phenomenon.

Abstract: There is considerable evidence to indicate that antigen-specific T helper cells and B cells recognize the same antigen in quite different ways. For instance, native and denatured forms of the same protein are highly cross-reactive antigens as recognized by helper and proliferating T cells, whereas they are completely noncrossreactive at the B cell level1–3, Furthermore, although B cells can readily be shown to bind conventional soluble antigens4, helper T cells cannot5,6; however, after antigen processing by syngeneic Ia-positive macrophages, antigen-dependent binding of helper T cells to macrophages has been demonstrated7,8. Data such as these have led to the postulation that B cells recognize intact, unprocessed antigen, whereas helper T cells recognize processed antigen presented in the context of macrophage Ia antigens. This postulation presents some difficulties for how T-B collaboration works, especially if antigen is important in bridging the 2 cells types as has been proposed in the hapten-carrier system first described by Mitchison9. A mechanism of T-B collaboration via antigen bridging has been postulated10 which involves the processing of antigen by antigen-specific B cells and subsequent presentation of the antigen, in the context of the B cell IA, to antigen-specific helper T cells.

Abstract: Several surface molecules appear to be involved in antigen recognition by human T lymphocytes including the monomorphic 20/25K T3 structure present on all mature T lymphocytes and the subset-specific associative recognition elements, T4 and T8 (refs 1–8). More recently, Ti1, a clonally unique antigen recognition structure comprised of a 49,000 molecular weight (49K) α-chain and a 43K β-chain, linked to T3 was identified on a major histocompatibility complex (MHC) class I specific T8+ T-cell clone, CT8III (ref. 9). To determine whether analogous receptor molecules could be found on other T-cell clones of differing specificity, we produced monoclonal antibodies against a clonal structure (Ti2) on an MHC class II specific T4+ lymphocyte, CT4II, derived from the same donor as CT8III. The Ti2 structure on CT4II is shown here to be a disulphide-linked heterodimer like Ti1 on CT8III and is composed of summits of similar molecular weight. Monoclonal antibodies against Ti2 or Ti1 block antigen specific functions of the respective clone without showing any cross-reactivity. These findings suggest that each T lymphocyte, regardless of subset derivation or specificity, uses an analogous Ti heterodimer for antigen specific function. The latter is linked to T3 and expressed on the cell surface at an identical density (30,000–40,000 sites per cell).

Abstract: We examined the ability of a set of cloned chicken ovalbumin (cOVA)-specific, Id-restricted, T cell hybridomas to produce interleukin-2 in response to cOVA presented by the Ia+ B cell lymphoma line, A20-2J Although viable A20-2J cells presented native, denatured, and fragmented cOVA more or less equally well, A20-2J cells that were glutaraldehyde-fixed could present only enzymatically or chemically fragmented cOVA These results suggest that antigen fragmentation may be both necessary and sufficient to define accessory cell processing of soluble antigens so that they may be recognized in association with I-region molecules by T cells

Abstract: Monoclonal antibody GK1.5 recognizes a determinant, designated L3T4a, on the murine T cell surface molecule L3T4. The expression of L3T4a by functional murine T cell clones appears to correlate primarily with class II MHC antigen reactivity rather than with functional phenotype. In previous studies, antigen-specific cytolysis by a cloned class II MHC antigen(I-Ak)-reactive CTL line was found to be blocked entirely by monoclonal antibody (mAb) GK1.5, at a step before the lethal hit. In the present studies, we demonstrate that mAb GK1.5 profoundly blocks antigen-specific proliferation and release of lymphokines by cloned murine class II MHC antigen-reactive helper T lymphocyte (HTL) lines. Analysis of cloned T cell hybridomas, however, suggests that there exists clonal heterogeneity in the degree of inhibition of class II MHC antigen-specific function by mAb GK 1.5. Finally, we present evidence that mAb GK1.5 blocks class II MHC antigen-specific function by blocking class II MHC antigen-specific binding. The data presented here lend considerable support to the concept both that L3T4 and the human Leu-3/T4 molecules are similar and that L3T4 plays a role in class II MHC antigen-reactivity by murine T cells.