Tissue resident memory T cells (TRMs) are retained within tissues, are phenotypically and functionally distinct from the circulating T cells and have been associated with protection against several pathogens. Pulmonary immunization of mice with recombinant influenza A viruses (rIAV) expressing the p25 CD4⁺ T cell epitope of the Mycobacterium tuberculosis (Mtb) Ag85B protein (PR8.p25 and X31-p25) protects mice against Mtb challenge. Using a model of adoptive transfer of P25 TCR transgenic CD4⁺ T cells, we found that the p25-specific T cells induced by rIAV vaccine persist in the lung parenchyma long after the virus is cleared and have the location, phenotypic and transcriptional characteristics of TRMs. Treatment of mice previously immunized with rIAV vaccine with the sphingosine-1-phosphate receptor modulator, FTY720, 3 days prior and during the first 17 days of Mtb challenge had no impact on the number of P25 TRMs found in the lung parenchyma while inducing marked reduction of the circulating T cells. More importantly mice immunized with the rIAV vaccine were protected against Mtb challenge even when circulating T cells were highly depleted by FTY720 treatment. Moreover, the presence of lung TRMs induced by the rIAV vaccine were able to overcome the increased susceptibility to Mtb infection observed in the mice treated with FTY720 due to the delayed recruitment of T cells from circulation into the lungs.

These results demonstrate that the protection against tuberculosis induced by pulmonary delivered rIAV vaccine is associated with the development of lung resident CD4+ memory T cells.

Support: NHMRC and Rebecca L. Cooper Medical Research Foundation.