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¹ Department of Immunobiology, ² Department of Cell Biology, ³ Howard Hughes Medical Institute, and ⁴ Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520
⁵ Department of Immunology and Microbial Sciences, Scripps Research Institute, La Jolla, CA 92037

CORRESPONDENCE Joe Craft: joseph.craft{at}yale.edu

The role of specialized follicular helper T (T_FH) cells in the germinal center has become well recognized, but it is less clear how effector T cells govern the extrafollicular response, the dominant pathway of high-affinity, isotype-switched autoantibody production in the MRL/MpJ-Fas^lpr (MRL^lpr) mouse model of lupus. MRL^lpr mice lacking the Icos gene have impaired extrafollicular differentiation of immunoglobulin (Ig) G⁺ plasma cells accompanied by defects in CXC chemokine receptor (CXCR) 4 expression, interleukin (IL) 21 secretion, and B cell helper function in CD4 T cells. These phenotypes reflect the selective loss of a population of T cells marked by down-regulation of P-selectin glycoprotein ligand 1 (PSGL-1; also known as CD162). PSGL-1^lo T cells from MRL^lpr mice express CXCR4, localize to extrafollicular sites, and uniquely mediate IgG production through IL-21 and CD40L. In other autoimmune strains, PSGL-1^lo T cells are also abundant but may exhibit either a follicular or extrafollicular phenotype. Our findings define an anatomically distinct extrafollicular population of cells that regulates plasma cell differentiation in chronic autoimmunity, indicating that specialized humoral effector T cells akin to T_FH cells can occur outside the follicle.

Abbreviations used: AFC, antibody-forming cell; AID, activation-induced cytidine deaminase; CGG, chicken globulin; CSR, class switch recombination; GC, germinal center; ICOS, inducible T cell co-stimulator; MRL^lpr, MRL/MpJ-Fas^lpr; NP, nitrophenyl; NZB/W F1, (NZB/BINJ x NZW/LacJ) F1; P-lig, P-selectin ligand; PSGL-1, P-selectin glycoprotein ligand 1; RIP-LTβ, rat insulin promoter-driven lymphotoxin and β; T_FH cell, follicular helper T.

B.R. Marks and L.D. DiPlacido contributed equally to this paper.

J.M. Odegard's present address is Dept. of Immunology, University of Washington, Seattle, WA 98195.

C. Dong's present address is Dept. of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030.

© 2008 Odegard et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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