title: Tolerance induction in memory CD4 T cells requires two rounds of antigen-specific activation.
abstract: A major goal for immunotherapy is to tolerize the immune cells that coordinate tissue damage in autoimmune and alloantigen responses. CD4 T cells play a central role in many of these conditions and improved antigen-specific regulation or removal of these cells could revolutionize current treatments. A confounding factor is that little is known about whether and how tolerance is induced in memory CD4 T cells. We used MHC class II tetramers to track and analyze a population of endogenous antigen-specific memory CD4 T cells exposed to soluble peptide in the absence of adjuvant. We found that such memory T cells proliferated and reentered the memory pool apparently unperturbed by the incomplete activation signals provided by the peptide. Upon further restimulation in vivo, CD4 memory T cells that had been previously exposed to peptide proliferated, provided help to primary responding B cells, and migrated to inflamed sites. However, these reactivated memory cells failed to survive. The reduction in T-cell number was marked by low expression of the antiapoptotic molecule B cell lymphoma 2 (Bcl2) and increased expression of activated caspase molecules. Consequently, these cells failed to sustain a delayed-type hypersensitivity response. Moreover, following two separate exposures to soluble antigen, no T-cell recall response and no helper activity for B cells could be detected. These results suggest that the induction of tolerance in memory CD4 T cells is possible but that deletion and permanent removal of the antigen-specific T cells requires reactivation following exposure to the tolerogenic antigen.
authors.affiliation: Howard Hughes Medical Institute, andIntegrated Department of Immunology, National Jewish Health, Denver, CO 80206;
authors.forename: Alexandria
authors.initials: A
authors.lastname: David
authors.affiliation: Howard Hughes Medical Institute, andIntegrated Department of Immunology, National Jewish Health, Denver, CO 80206;
authors.forename: Frances
authors.initials: F
authors.lastname: Crawford
authors.affiliation: Centre for Immunobiology Institute of Infection, Immunity and Inflammation, Glasgow University, Glasgow G12 8TA, United Kingdom; and.
authors.forename: Paul
authors.initials: P
authors.lastname: Garside
authors.affiliation: Howard Hughes Medical Institute, andIntegrated Department of Immunology, National Jewish Health, Denver, CO 80206;Department of Medicine,Program in Biomolecular Structure, and.
authors.forename: John W
authors.initials: JW
authors.lastname: Kappler
authors.affiliation: Howard Hughes Medical Institute, andIntegrated Department of Immunology, National Jewish Health, Denver, CO 80206;Department of Medicine,Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045 marrackp@njhealth.org Megan.MacLeod@glasgow.ac.uk.
authors.forename: Philippa
authors.initials: P
authors.lastname: Marrack
authors.affiliation: Centre for Immunobiology Institute of Infection, Immunity and Inflammation, Glasgow University, Glasgow G12 8TA, United Kingdom; and marrackp@njhealth.org Megan.MacLeod@glasgow.ac.uk.
authors.forename: Megan
authors.initials: M
authors.lastname: MacLeod
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000941:Antigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D020169:Caspases / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005802:Genes, MHC Class II / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000941:Antigens; D020169:Caspases