Partial role of CXCR3 in the migration of CD4 T cells into the lung of TB infected mice

Abstract

Abstract Mycobacterium tuberculosis (Mtb) is the leading cause of death by infectious disease worldwide. In order to develop effective vaccination strategies for Mtb, it is critical to understand the properties of host-protective CD4 T cells. We have shown that various subsets of Mtb-specific Th1 cells display dramatically different lung migratory abilities. CXCR3+ Th1 cells migrate into the lung and control Mtb infection, while CX3CR1+ Th1 cells are retained in the lung-associated blood vasculature and do not suppress bacterial growth in vivo. However, little is know about the precise role of different chemokine receptors in the entry of Mtb-specific Th1 cells into the lung. Here we quantify the individual contributions of several chemokine receptors in the pulmonary migration of Th1 cells by performing in vivo migration experiments after adoptive transfer of WT and CCR KO Mtb-specific lung effector T cells into infection matched WT recipients. Firstly, we find that Th1 cells migration into the lung is pertussis toxin sensitive, indicating that G-protein coupled receptors are required. We find that while CXCR6 is highly expressed in Th1 cells capable of migrating into the lung, it has no role in their entry. Likewise, CCR2 had no role in Th1 cell migration into Mtb infected lungs. Interestingly, CXCR3−/− CD4 T cells displayed only a ~30% reduction compared to WT cells 16 hours after transfer. Although CXCR3 and CXCR6 are defining markers expressed on all lung-homing Mtb-specific Th1 cells, our results indicate that additional chemokine receptors are involved in their migration. Identification of new mechanisms governing the migration of Mtb-specific Th1 cells into the lung may give important insight into T cell dependent immunity to Mtb infection.