Is the chemokine receptor CXCR3 required for the retention of lung-resident memory T cells following a pulmonary TB vaccine?
Armitage, E.1, Quan, D.1, Florido, M.1, Palendira, U.2, Triccas, J.2, Stambas, J.3, Britton, W.1
1Centenary Institute, Sydney, Australia, 2University of Sydney, Sydney, Australia, 3Deakin University, Geelong, Australia
Recent evidence indicates that lung-resident memory (TRM) CD4+ T cells contribute to vaccine-induced protective immunity against Mycobacterium tuberculosis (Mtb). The recombinant influenza A virus (rIAV) vaccine, PR8.p25, that expresses the Mtb p25 CD4+ T cell epitope induces specific TRMs in the lungs. Analysis of gene expression of these TRM identified 245 differentially regulated genes in TRM, including 44 that were not differentially expressed in effector or effector memory T cells. The TRM expressed the gene encoding CXCR3, that is considered important for T cell entry imto the lungs, but its requirement for retention of TRM is unknown. Using CXCR3 reporter mice, we confirmed that CXCR3 was expressed on rIAV-induced CD4+ T cells recruited to the lungs, and at 6 weeks, a higher proportion of antigen-specific CD4+ TRM expressed CXCR3 than total lung CD4+ T cells. However, CXCR3 was not required for recruitment of CD4+ T cells, as CXCR3-/- mice showed equivalent antigen-specific CD4+ T cell responses in the lungs to WT mice following rIAV-PR8.p25. Surprisingly, CXCR3-deficient mice retained more p25-specific CD4+ TRM in the lungs than WT mice at 6 weeks. When CXCR3-deficient and WT P25 CD4+ T cells were co-transferred prior to PR8.p25 immunization, initial recruitment of p25-specific T cells into the lungs was independent of CXCR3, but by 6 weeks, the number of CXCR3-deficient CD4+ T cells was significantly reduced compared to WT T cells, and CXCR3-/- TRM were markedly reduced. Therefore, although CXCR3 expression provides a competitive advantage for the induction of CD4+ TRM in the lungs, this is not essential for CD4+ T cell retention of CD4 TRM in the lungs following pulmonary immunization.