| MRL/MpJ-Faslpr (MRL/ Faslpr) mice develop a spontaneous lupus-like autoimmune syndrome with production of class-switched autoantibodies and spontaneous CD4 T cell activation. We sought to study the mechanisms of inflammatory and B cell-helper effector function mediated by CD4 T cells in lupus. Inflammatory cells infiltrate the kidneys of lupus mice, and we show here that these infiltrates are enriched for CD4 T cells expressing P-selectin glycoprotein ligand (PSGL)-1, and its P-selectin-binding modification, P-ligand; renal-infiltrating CD4 T cells also express CXC chemokine receptor (CXCR) 3 and the induced costimulatory molecule ICOS. Consistent with this data, CXC chemokine ligand (CXCL) 9, a ligand for CXCR3, is highly expressed in nephritic lupus kidneys. Lupus mice genetically deficient in Icos have greatly reduced renal inflammatory infiltrates. We show here that expression of PSGL-1, P-ligand, and CXCR3 on the surface of CD4 T cells does not require ICOS. However, CD4 T cell population expansion within the kidney and production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma, are ICOS-dependent.;Previous research in the lab has demonstrated that MRL/Fas lpr PSGL-1lo CD4 T cells have a B cell-helper phenotype, including production of interleukin (IL)-21, and the ability to help B cells class-switch and secrete immunoglobulin. Here we report that this subset expands in the lupus-prone mice MRL/MpJ-Fas ++ (MRL/Fas++), B6.Sle1| 2|3, and B6.Sle1|Yaa mice, but not in MRL/Fas++ Icos -/- mice; thus, their development is independent of the lpr mutation of fas, requires ICOS, and is a feature common to murine lupus. PSGL-1lo CD4 T cells are located within spontaneously forming extrafollicular foci (EF) and germinal centers (GC) of spleens from lupus-prone mice. They uniquely express programmed death (PD)-1, CXCR4, CXCR5, GATA-3, BCL-6, and are primed to secrete IL-4 and IL-21 upon stimulation. PSGL-1lo, but not PSGL-1hi, CD4 T cells undergo CXCL 13-mediated chemotaxis. However, PSGL-1lo CD4 T cells do not migrate towards CXCL 12, which is likely due to their high expression of regulator of G-protein signaling (RGS) 16.;These studies describe the development pro-inflammatory and B cell-helper CD4 T cell effector subsets in lupus, and the critical but complex role that ICOS plays in their development. |
