ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity

J Exp Med. 2008 Nov 24;205(12):2873-86. doi: 10.1084/jem.20080840. Epub 2008 Nov 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • Antigens, Differentiation, T-Lymphocyte / genetics
  • Antigens, Differentiation, T-Lymphocyte / immunology*
  • Autoimmunity / immunology*
  • Cell Differentiation / physiology
  • Chemokines / immunology
  • Disease Models, Animal
  • Germinal Center / cytology
  • Germinal Center / immunology
  • Immunoglobulin Class Switching
  • Immunoglobulin G / biosynthesis*
  • Immunoglobulin G / immunology
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukins / immunology*
  • Lupus Erythematosus, Systemic / immunology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Knockout
  • Plasma Cells / cytology
  • Plasma Cells / physiology
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / immunology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Helper-Inducer / immunology*

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CXCR4 protein, mouse
  • Chemokines
  • Icos protein, mouse
  • Immunoglobulin G
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukins
  • Membrane Glycoproteins
  • P-selectin ligand protein
  • Receptors, CXCR4
  • interleukin-21