Contribution of antigen-presenting cell major histocompatibility complex gene products to the specificity of antigen-induced T cell activation

Abstract

Previous studies from our laboratory showed that B 10.A mice are high responders to pigeon cytochrome c fragment 81-104, whereas B 10.A(5R) mice are low responders. In the present studies, the C-terminal cyanogen bromide cleavage fragment and homologous synthetic peptides of tobacco horn worm moth cytochrome c were shown to be immunogenic in both B10.A and B10.A(5R) mice. These strains, however, showed different patterns of cross-reactivity when immune lymph node T cells were stimulated with cytochrome c fragments from other species. To examine the two patterns of responsiveness at a clonal level, cytochrome c fragment-specific T cell hybridomas were made and found to secrete interleukin 2 in response to antigen. The patterns of cross- reactivity of these B 10.A and B 10.A(5R) clones were similar to that seen in the whole lymph node population. Surprisingly, when these clones were tested for major histocompatibility complex (MHC)-restricted antigen recognition, they were all found to respond to antigen with both B10.A and B10.A(5R) antigen-presenting cells (APC). Furthermore, the cross-reactivity pattern appeared to be largely determined by the genotype of the APC, not the genotype of the T cell clone. That is, a given T cell clone displayed a different fine specificity when assayed with B10.A or B10.A(5R) APC. This observation indicates that the APC MHC gene product and antigen interact during the stimulation of the T cell response and that as a consequence the specificity of antigen-induced T cell activation is influenced by these MHC gene products. (During the preparation of this manuscript it has come to our attention that results similar to our own, concerning the fine specificity of cytotoxic T cell clones, have been obtained by Dr. T. R. Hunig and Dr. M. J. Bevan, Massachusetts Institute of Technology, Boston, MA. T. R. Hunig and M. J. Bevan. 1981. Specificity of T-cell clones illustrates altered self hypothesis. Nature. 294:460.)

Hepatitis C Virus Core Protein Leads to Immune Suppression and Liver Damage in a Transgenic Murine Model

“…The expression of genes under the control of the CD2 promoter have been detected in T cells (21,54,67) (9,10,51), the HCV core-induced immune dysregulation may depend for its intracellular expression on immune cells rather than hepatocytes. Furthermore, the magnitude of allogeneic responses in CBA (H-2 k ) versus BALB/c (H-2 d ) mice was similar to that in C57BL/6 (H-2 b ) versus BALB/c (H-2 d ) mice (24). This suggests that suppression of T-lymphocyte responses in core TG mice was not due to minor differences in the genetic background of our murine model but to the immunomodulatory function of HCV core.…”

Mechanism responsible for the induction of I-J restriction on TS3 suppressor cells.

“…(a) For both Th and Tsa generation, antigen must be presented in the context of MHC determinants on an adherent antigen-presenting cell (6)(7)(8)30). (b) In H-2 heterozygous Fa mice, conventional antigen priming generates two distinct populations of helper or suppressor cells, each specific for antigen in the context of one of the parental H-2 haplotypes (31,32).…”

Production of autoreactive I region-restricted T cell hybridomas.

“…After 2 d of culture, supernatants were collected and assayed for IL-2 content in a secondary culture by using HT-2 cells, an IL-2-dependent T cell line developed by Dr. James Watson, University of Auckland, Auckland, New Zealand, and provided by Dr. Phillipa Marrack, National Jewish Hospital, Denver, CO. Results and Discussion Our initial attempts at the production of autoreactive T cell hybridomas involved the fusion of blasts obtained from primary or secondary syngeneic MLR cultures with the BW 5147 line, using the methods described by Kappler et al (9) and Heber-Katz et al (8). No hybridomas specific for syngeneic stimulator cells could be isolated from such fusions.…”