CXCR3 is preferentially expressed on encephalitogenic Th1 cells [13, 32, 33], and on T cells that infiltrate Talazoparib order MS and EAE lesions [4-6, 9-11], making it a logical therapeutic target for the suppression of Th1-mediated inflammatory demyelinating disease. We found that, even in that special circumstance, blockade of CXCR3, or neutralization

of its primary ligand, had no therapeutic impact on the clinical course of EAE. Similarly, CXCR3−/− Th1 cells were not compromised in their ability to transfer clinical EAE. In fact, WT recipients of CXCR3−/− Th1 cells, or CXCL10−/− recipients of WT Th1 cells, failed to recover following peak disease to the same extent as their WT counterparts (Fig. 2C and F). It is possible that widespread and diffuse parenchymal distribution of effector cells, as described by Muller et al. in MOG-immunized CXCR3−/− mice [17], results in increased axonal damage and long-term deficits. Of note, administration of a mAb specific for CXCR3 was found to be therapeutically beneficial in a Lewis rat model of EAE induced by the adoptive transfer of unpolarized myelin Osimertinib mw basic protein reactive T cells [10]. As in our study, the investigators did not administer Bordetella pertussis toxin (PT) to transfer recipients. The discrepancy between their results and ours

further underscores the heterogeneity of encephalitogenic T cells and reinforces our contention that the importance of a specific molecule as a therapeutic target is context dependent. Other laboratories Methocarbamol have previously reported that Th17 “sentinel” cells traverse the blood–brain barrier at the inception of EAE and release vasoactive substances that permit the subsequent infiltration of Th1 cells [26, 34, 35]. This raises the possibility that in our experimental

paradigms, neuroinflammation is initiated by a minor subpopulation of Th17 contaminants within the pool of IL-12-polarized donor cells. We deem this unlikely since we were unable to detect IL-17+ cells among IL-12-polarized donor T cells. Furthermore, we did not detect RORγt transcripts in mRNA extracted from donor cells immediately prior to adoptive transfer (data not shown). It has also been reported that CNS expression of ELR− CXC chemokines leads to the local accumulation of CXCR3+ Tregs [17, 36]. By extension, mice with a disrupted CXCR3/CXC chemokine pathway could be relatively susceptible to EAE due to a dearth of Tregs in target organ infiltrates. However, we found no difference in the percentage of FoxP3+ T cells in the CNS of WT and CXCL10−/− hosts with Th1-mediated EAE. Similarly, FoxP3+ donor cells occurred at the same frequency in the adoptive recipients of CXCR3−/− and WT Th1-polarized cells (data not shown). We believe that the most likely explanation for the dispensability of CXCR3/CXC chemokine interactions in the manifestation of Th1-mediated EAE lies in the complexity of chemokine pathways that arise at sites of neuroinflammation.