Nonresponsiveness and susceptibility to CTLA-4 of antigen-exposed CD4 T cells are not regulated by the Bcl-2 family of apoptotic mediators, but can be restored by IL-2.
Memory T cells are considered to be less dependent on costimulation and to respond more vigorously to TCR triggering compared to their naive counterparts. We and others, however, observed that memory CD4 T cells display nonresponsiveness to a variety of stimuli, including superantigens and soluble anti-CD3. We now report that CD28-derived costimulation can revert the nonresponsive state of antigen-exposed CD4 T cells. Interestingly, the rescuing effect of CD28 can be completely negated by CTLA-4 engagement. The malfunction of memory T cells is related to increased cell death; the viability can be restored by CD28 engagement and is negatively regulated by CTLA-4 engagement. Importantly, it has been reported that antigen-exposed T cells express lower levels of the anti-apoptotic mediator Bcl-2. In addition, CD28 costimulation was reported to upregulate the expression levels of Bcl-xL. We therefore examined the possible role of Bcl-2 family proteins in the nonresponsiveness of antigen-exposed CD4 T cells, and determined whether CTLA-4, in analogy to CD28, mediates its negative regulatory effects via the Bcl-2 family of apoptotic mediators. Our data indicate that neither the nonresponsiveness nor the susceptibility to CTLA-4 of antigen-experienced CD4 T cells are related to the expression levels of Bcl-2 or Bax. The rescuing effects of CD28, however, may be related to increased Bcl-xL levels. Addition of IL-2 normalizes the nonresponsiveness of memory CD4 T cells and renders these cells resistant to the negative effects of CTLA-4 engagement. Impaired IL-2 production is therefore likely to be the cause of the malfunction and CTLA-4 susceptibility of memory CD4 T cells.
Hamel
M E
ME
Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Leupers
T J
TJ
Kruisbeek
A M
AM
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D017209:Apoptosis; D018106:CD28 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000494:pharmacology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D051028:bcl-2-Associated X Protein
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; C494827:Bax protein, mouse; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000069594:Abatacept; D017493:Leukocyte Common Antigens