Louis A. Matis

Correlations between T-cell specificity and the structure of the antigen receptor.

The derived amino-acid sequences of the heterodimeric antigen receptors expressed by a series of murine T-cell clones are presented. A comparison of the receptor sequences indicates that several mechanisms for generating receptor diversity can influence T-cell specificity, including junctional diversity, combinatorial joining, and combinatorial chain associations.

The Fine Specificity of Antigen and la Determinant Recognition by T Cell Hybridoma Clones Specific for Pigeon Cytochrome c

The activation of proliferative T lymphocytes normally involves the simultaneous recognition of a particular foreign antigen and a particular Ia molecule on the surface of antigen-presenting cells, the phenomenon of major histocompatibility complex (MHC) restriction. An analysis of T cell clones specific for pigeon cytochrome c, from B10.A and B10.S(9R) strains of mice, revealed the unusual finding that several of the clones could respond to antigen in association with Ia molecules from either strain. Using these cross-reactive clones, we performed experiments which demonstrated that both the Ia molecule and the T cell receptor contribute to the specificity of antigen recognition; however, MHC-linked low responsiveness to tuna cytochrome c (an immune response gene defect) could not be attributed solely to the efficacy with which the Ia molecules associated with the antigen. These results imply that antigen and Ia molecules are not recognized independently, but must interact at least during the process of T cell activation.

Requirement for positive selection of gamma delta receptor-bearing T cells

The alpha beta and gamma delta T cell receptors for antigen (TCR) delineate distinct T cell populations. TCR alpha beta-bearing thymocytes must be positively selected by binding of the TCR to major histocompatibility complex (MHC) molecules on thymic epithelium. To examine the requirement for positive selection of TCR gamma delta T cells, mice bearing a class I MHC-specific gamma delta transgene (Tg) were crossed to mice with disrupted beta 2 microglobulin (beta 2M) genes. The Tg+beta 2M- (class I MHC-) offspring had Tg+ thymocytes that did not proliferate to antigen or Tg-specific monoclonal antibody and few peripheral Tg+ cells. This is evidence for positive selection within the gamma delta T cell subset.

Nodular lymphomas: current concepts.

The past several years have witnessed innovative approaches to clinical management as well as significant insights into the basic biology of the nodular lymphomas. Clinical studies have explored two apparently widely disparate approaches to the treatment of patients with nodular lymphoma. On the one hand, withholding initial therapy (watch and wait) has proved to be a viable option in the management of some patients. This approach has provided information regarding the natural history of disease, such as the relative incidence of spontaneous tumor regression vs. histologic transformation to more aggressive forms of lymphoma. Alternatively, recent data also suggest that the administration of intensive chemotherapy, shown to induce long-term remissions in a high percentage of patients with diffuse aggressive lymphomas, may also produce a significant number of durable remissions in at least certain histologic subtypes of nodular lymphomas. Clinical studies which attempt to achieve a synthesis of the above two approaches are currently in progress. Advances in immunology and molecular biology have also found application in the study of nodular lymphoma. Monoclonal antibodies have been employed diagnostically, as, for example, in detecting small numbers of persistent abnormal lymphoid clones in patients in apparent remission, and therapeutically, as exemplified by the clinical use in vivo of monoclonal antibodies directed against unique idiotypic determinants expressed by surface immunoglobulin on the malignant B lymphocytes. The demonstration of the immunoglobulin gene rearrangements in nodular lymphoma cells has established a more definitive criterion for their phenotypic characterization. Finally, molecular cloning of the breakpoint of the t(14; 18) chromosome translocation frequently found in nodular lymphoma cells has led to the identification of a potential new transforming gene which could be activated as a direct consequence of its rearrangement in proximity to the immunoglobulin in heavy chain gene locus.

Cloning with antigens and interleukin 2 of murine T lymphocytes having distinct functions.

Publisher Summary This chapter describes cloning with antigens and interleukin 2 of murine t lymphocytes having distinct functions. Critical to developing a reproducible methodology for the generation of murine T cell clones is the fact that all T cell proliferation ultimately requires the interaction of interleukin-2 (IL-2) with its receptor (IL-2R) on the T cell surface. In this regard, two phenotypic characteristics of T cells are presented. The first bears upon the variable requirement for the addition to the culture medium of exogenous IL-2 as a growth factor for the propagation of T cell clones. Some T cell clones of both L3T4+ Lyt2- and L3T4- Lyt2 + phenotypes have the capacity to produce their own IL-2 following antigen activation and thus can be maintained in vitro by serial stimulation with appropriate antigen in the absence of exogenous growth factors. Among clones of this type, ones find that L3T4+ cells generally produce greater amounts of IL-2 than Lyt2 + clones. Other T cell clones manifest an absolute requirement for the addition of an exogenous source.

The Influence of MHC Gene Products on the Generation of an Antigen‐Specific T‐Cell Repertoirea

We have previously described the B10.A pigeon cytochrome c-specific response in terms of clonal phenotypes and T-cell receptor (TcR) gene usage. All B10.A T-cell clones studied respond to antigen in association with syngeneic B10.A APCs and cross-react to antigen in association with one or two allogeneic variants of the I-E-encoded MHC molecules. In congenic strains of mice expressing these allogeneic MHC alleles [B10.A(5R) and B10.S(9R)], pigeon cytochrome c-specific T cells exhibit very similar MHC cross-reactivities. Our goal was to determine whether the same MHC cross-reactive T-cell clones were expressed in each appropriate strain, or whether each T-cell repertoire was unique. The results indicate that identical V alpha-J alpha and V beta-J beta combinations were expressed by the major pigeon cytochrome c-specific response phenotype in B10.A and B10.A(5R) mice. Previous functional data supports this overlap in expressed T-cell clones. B10.A and B10.S(9R) mice exhibit similar response phenotypes to pigeon cytochrome c but express distinctly different TcR genes. The results of these studies support the existence of at least two different mechanisms in determining MHC-linked immune response polymorphisms.

Helper T Cells Specific for Protein Antigens: Role of Self Major Histocompatibility Complex and Immunoglobulin Gene Products

Antibody responses to most antigens are dependent on the cooperative interaction of two distinct populations of lymphocytes. B lymphocytes are the precursors to antibody forming cells; their ability to produce antibody is dependent on helper T lymphocytes (Th). In classical studies of helper T cell function, B cells specific for haptens have been stimulated with hapten-protein conjugates, and the role of protein carrier-primed helper T cells measured (1). In such studies, the hapten must be physically linked to the carrier protein (1,2), and the helper T cell specifically primed to the carrier used for secondary immunization (1,2). Using this system, Katz and coworkers (3) made the surprising discovery that Th and B lymphocytes needed to be identical in the I region of the major histocompatibility complex (MHC) in order to cooperate effectively. Subsequent studies by a number of investigators have demonstrated that Th cells are selected during their development for the ability to recognize particular MHC encoded antigens as self, and that such Th cells will not respond to antigen except in the context of the MHC encoded antigen for which they are specific (4). This phenomenon has been termed MHC restriction.