Phil Lake

Antigen-specific human T-lymphocyte clones Genetic restriction of influenza virus-specific responses to HLA-D region genes

Human T lymphocytes, primed in vitro to influenza virus, were cloned by limiting dilution and expanded using medium containing interleukin 2 and feeder cells. A detailed analysis of the genetic requirements for induction of T-cell proliferation was conducted using a panel of cells from unrelated donors and two families who had previously been extensively phenotyped for HLA region antigens. Clones obtained from a Dw1, Dw3 individual required Dw1,DR1 histocompatibility for successful presentation of viral antigens by antigen-presenting cells. The antigen-presenting ability segregated with HLA-B,D,DR in an informative HLA-A/B recombinant individual. In contrast, some TLCs responded to antigen presented by cells that did not share known HLA antigens, and in one informative family, reactivity did not segregate with HLA. None of the T-cell clones reacted to allogeneic cells in the absence of antigen, suggesting that the TLCs do not bear receptors that recognize both influenza virus and alloantigen. In antibody-blocking studies, Dw1, DR1-restricted clones were blocked by all monoclonal anti-DR framework antibodies. The non-HLA-restricted TLCs were blocked by some, but not all, of the anti-DR framework monoclonal antibodies. These results confirm and extend the role of HLA-D region gene products in antigen presentation and also provide evidence that yet undefined cell interaction products, which may include hybrid structure, are able to participate in antigen-specific proliferative responses by human T cells.

Antibody response induced in vitro to the cell-surface alloantigen thy-1.

MANY important antibody responses are provoked by antigens on the surfaces of nucleated cells and, in spite of wide interest, little is known of the immunobiology of these responses. Alloantigens comprise an intriguing class of surface antigens because they may stimulate antibody production by B cells as well as target-cell killing by T cells and also because alloantigens are themselves intimately involved in the immunological recognition of other cellular antigens, such as viral antigens1, autoantigens2, surface-bound haptens3, other allo-antigens4 and tumour-associated antigens5. Studies of antibody responses in vitro, involving potent xenoantigens, have contributed greatly to the understanding of cellular and molecular interactions in immunity6. This has suggested the potential of such systems for the study of responses to weaker antigens of nucleated cells. In this report I define such an experimental approach with the induction in vitro of primary and secondary responses to the murine alloantigen Thy–1 as measured with a modified plaque-forming cell (PFC) assay, developed from the method of Fuji et al.7.

Functional interactions of human and murine lymphoid cells: I. Analysis of primary and secondary responses

In this study human T-cell responses against murine alloantigens were analyzed. The results show that optimal primary responses are obtained from peripheral blood mononuclear cells only when murine splenic adherent cells (SAC) were used as antigen. Further analysis revealed that human T cells were able to respond directly to murine cells without the need for antigen reprocessing; however, human interleukin 1 (IL-1) was required for optimal stimulation. In contrast, secondary proliferative responses to murine cellular antigens could be induced from primed T cells even in the absence of SAC and/or IL-1. These proliferative responses, and in addition, cytotoxic T-cell responses, were specific for the priming antigen. Long-term human T-cell lines specific for murine alloantigens were found to replace the need for murine T cells in antigen-specific murine B-cell responses to sheep red blood cells. The mechanism of help delivered by the human T cells appeared to be by the release of nonspecific helper-T-cell factors. The evidence presented for this is the inability of these cells to stimulate cells from mice that express the X chromosome B-cell defect xid.

Multiple Genes Control Human Immune Responses

Since the initial description of Ir genes by McDevitt and Benacerraf1 much discussion has centered around the nature of the Ir gene products and the mechanisms by which they control immune responses.2 Early work by Shevach and Rosenthal indicated that the antigen presenting cell seemed to control T-cell recognition by presenting only certain portions of the antigen,3,4 More recently, with the work of Berzofsky,5 Sercarz,6 and others it has become clear that Ir gene effects are mediated at the level of the antigenic epitope recognized by the T-cell and that Ia antigens are in fact, the Ir gene products.2 The resolving power of such systems depends upon the fact that it is possible to look at immune responses controlled by discrete portions of the murine MHC by using congenic strains. In contrast, work on human Ir genes has lagged far behind for obvious reasons.

The IL-1 Pathway in T Cell Activation

Almost without exception, normal T cells or their progeny require accessory cells (AC) or their products for activation and proliferation induced by mitogens, antigens and soluble anti-idiotypic antibodies. Despite many years of effort, the role of MHC products, interleukin-1 (IL-1) and other possible signalling systems of AC which promote T cell responses remain unclear. In this report we discuss a new IL-l-dependent human T cell activation system which contrasts with and illuminates properties of T cell activation pathways regulated by AC. The results show that IL-1 can promote IL-2 receptor expression on T cells and that signals other than IL-1 are required for T cell responses to lectin mitogens.

Generation of Monoclonal Human Antigen-specific T Cell Helper Factors

ABSTRACT Antigen-specific human helper T cell lines and clones have been generated to various influenza viral antigens. Help for antibody production by human B cells is mediated by soluble helper factors. The helper factors are antigen-specific and appear to be genetically restricted to class II-type antigens. Helper lines and clones also generate non-specific helper and suppressor-inducer factors.