Paradoxically, IFN-γ-producing cells were more prevalent than IL-17-producing cells in CNS mononuclear fractions from CXCR3−/− and CXCL10−/−, as well as WT, mice with MOG-induced EAE (Fig. 1D and H). Enrichment of IFN-γ producers within the CNS could be secondary to preferential trafficking, survival,

and/or expansion of Th1 over Th17 cells. If so, the data in Figure 1 would insinuate that MOG-specific Th1 cells cross the blood–brain barrier and are retained in the brain and SC by a CXCR3/CXCL10-independent mechanism. Alternatively, the majority of CNS-infiltrating IFN-γ-producing T cells could represent transformed Th17 cells that Selleckchem Raf inhibitor acquire Th1-like characteristics within the CNS microenvironment (the so-called “ex-Th17” cells) [28]. Th17 cells have been shown to access the CNS via a CCR6-CCL20-dependent pathway, which could explain the dispensability of CXCR3-CXC chemokine interactions for the development of IFN-γ-rich neuroinflammatory infiltrates in MOG-immunized mice [26]. In support of the latter hypothesis, mRNA for IL-17A, RORγt, and

CCL20 was upregulated in the CNS of CXCR3−/−, CXCL10−/−, and WT mice with EAE (Fig. 1I and J). Next, we sought to directly compare the relative dependence of MOG-specific Th1 and Th17 cells on CXCR3/ELR− CXC chemokine interactions for their encephalitogenicity. MOG-primed CXCR3−/− T cells exhibited similar cytokine profiles to their WT counterparts following culture under either Th1- or Th17-polarizing HM781-36B cell line conditions (Fig. 2A). As expected, MOG-primed, IL-23-polarized CXCR3−/− Th17 cells were

as efficient as WT Th17 cells in trafficking to the CNS and inducing clinical EAE following adoptive transfer into naïve syngeneic WT hosts (Supporting Information Fig. 1 and Fig. 2B). Surprisingly, IL-12-polarized CXCR3−/− Th1 cells showed no defect in EAE induction (Fig. 2C). In fact, recipients of CXCR3−/− Th1 cells underwent a prolonged disease course with attenuated remission compared to recipients of WT Th1 cells. CXCR3−/− Th1 cells accumulated in the CNS in comparable numbers to WT Th1 donor cells, and the majority of Non-specific serine/threonine protein kinase CXCR3−/− donor T cells in the SC were IFN-γ+ (Fig. 2D). CXCL10 is a dominant CXCR3 ligand in the CNS of the EAE models employed in our studies; C57BL/6 mice do not produce functional CXCL11 protein and CXCL10 is significantly upregulated in the inflamed CNS of MOG-immunized mice (Fig. 2E). In parallel experiments, CXCL10−/− and WT hosts exhibited a comparable degree of susceptibility to EAE mediated by WT Th1-polarized, MOG-specific effector T cells (Fig. 2F). Similar to WT recipients of CXCR3−/− Th1 cells, CXCL10−/− recipients of WT Th1 cells experienced a relatively severe disease course. Mice that are genetically deficient in an immunological molecule can develop compensatory pathways as they mature.