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Anergy in Memory CD4⁺ T Cells Is Induced by B Cells^1,2

Sarat K. Dalai^3,*, Saied Mirshahidi^4,*, Alexandre Morrot, Fidel Zavala and Scheherazade Sadegh-Nasseri^5,*

^* Department of Pathology, Johns Hopkins School of Medicine and Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore MD 21205

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01GM53549 and R01AI063764 to S.S.-N.

² Portions of this work were presented (poster and oral) by S. K. Dalai at "Experimental (EB) Biology 2005," the American Association of Immunologists (AAI) 2005 Annual Meeting, April 2–6, 2005, San Diego, CA and at "Immunology 2007," 94th Annual Meeting of the AAI, May 18–22, 2007, Miami Beach, FL.

³ Current address: Walter Reed Army Institute of Research, Silver Spring, MD 20910.

⁴ Current address: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.

⁵ Address correspondence and reprint requests to Dr. Scheherazade Sadegh-Nasseri, Department of Pathology, Johns Hopkins School of Medicine, Johns Hopkins University, Ross Research Building, Room 664, 720 Rutland Avenue, Baltimore, MD 21205-2191. E-mail address: ssadegh{at}jhmi.edu

⁶ Abbreviations used in this paper: LN, lymph node; B6, C57BL6; cOVA, chicken OVA; DC, dendritic cell; DT, diphtheria toxin; DTR, diphtheria toxin receptor; Tg, transgenic; Treg, regulatory T cell.