Non-responsiveness of antigen-experienced CD4 T cells reflects more stringent co-stimulatory requirements.
We recently reported that previously activated T cells, irrespective of the nature of the first stimulus they encountered, are unable to respond to Staphylococcal enterotoxin B (SEB), nor to soluble anti-CD3 monoclonal antibody (mAb) presented by splenic antigen-presenting cells (APC). Such previously activated T cells are, however, fully capable of responding to plate-bound anti-CD3 plus splenic APC. These data suggest differential integration of the T-cell receptor (TCR) and co-stimulatory signalling pathways in naive versus antigen-experienced T cells. Consistent with this hypothesis, anti-CD28 mAb restores the proliferative capacity of resting ex vivo CD45RBlo CD4+ T cells (representing previously activated T cells) to both soluble anti-CD3 mAb and SEB. Interestingly, mAb-mediated engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) completely negates the rescue effects mediated by anti-CD28 mAb in CD45RBlo cells. Nevertheless, the non-responsiveness of CD45RBlo CD4+ T cells cannot be reversed by anti-CTLA-4 Fab fragments, indicating that it is not related to negative regulatory effects of CTLA-4 engagement itself. Interestingly, the addition of interleukin-2 (IL-2) restores the proliferative capacity of CD45RBlo CD4+ T cells to SEB and soluble anti-CD3 mAb. Moreover, when rescued by IL-2, the cells are less susceptible to the negative regulatory effects of CTLA-4 engagement. Together, these findings suggest that the non-responsiveness of CD45RBlo CD4+ T cells to certain stimuli may be related to inadequate TCR signalling, primarily affecting IL-2 production.
Hamel
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ME
Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Noteboom
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Kruisbeek
A M
AM
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000938:Antigen-Presenting Cells; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004768:Enterotoxins / Q000494:pharmacology; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D017493:Leukocyte Common Antigens; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013211:Staphylococcus aureus; D018089:Superantigens / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D004768:Enterotoxins; D018796:Immunoconjugates; D007376:Interleukin-2; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; D000069594:Abatacept; D017493:Leukocyte Common Antigens