Anergy in memory CD4+ T cells is induced by B cells.
Induction of tolerance in memory T cells has profound implications in the treatment of autoimmune diseases and transplant rejection. Previously, we reported that the presentation of low densities of agonist peptide/MHC class II complexes induced anergy in memory CD4(+) T cells. In the present study, we address the specific interaction of different types of APCs with memory CD4(+) T cells. A novel ex vivo anergy assay first suggested that B cells induce anergy in memory T cells, and an in vivo cell transfer assay further confirmed those observations. We demonstrated that B cells pulsed with defined doses of Ag anergize memory CD4 cells in vivo. We established that CD11c(+) dendritic cells do not contribute to anergy induction to CD4 memory T cells, because diphtheria toxin receptor-transgenic mice that were conditionally depleted of dendritic cells optimally induced anergy in memory CD4(+) T cells. Moreover, B cell-deficient muMT mice did not induce anergy in memory T cells. We showed that B2 follicular B cells are the specific subpopulation of B cells that render memory T cells anergic. Furthermore, we present data showing that anergy in this system is mediated by CTLA-4 up-regulation on T cells. This is the first study to demonstrate formally that B cells are the APCs that induce anergy in memory CD4(+) T cells.
Dalai
Sarat K
SK
Department of Pathology, Johns Hopkins School of Medicine, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore MD 21205, USA.
Mirshahidi
Saied
S
Morrot
Alexandre
A
Zavala
Fidel
F
Sadegh-Nasseri
Scheherazade
S
D000818:Animals; D000938:Antigen-Presenting Cells; D015703:Antigens, CD / Q000235:genetics; D001402:B-Lymphocytes / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes; D060908:CTLA-4 Antigen; D017635:Clonal Anergy / Q000276:immunology*; D018920:Coculture Techniques; D007156:Immunologic Memory; D051379:Mice; D015854:Up-Regulation
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse