The Recruitment and Transcriptional Profile of Tuberculosis Vaccine-Induced Lung Resident Memory T Cells

Tuberculosis (TB) is among the deadliest of human infectious diseases. Efforts to end the global TB epidemic require new vaccines to protect people against pulmonary TB and stop the spread of the disease. To do this, it is essential to understand the immune responses that prevent Mycobacterium tuberculosis (Mtb) infection. Pulmonary delivery of the recombinant influenza A virus vaccine PR8.p25, which expresses the p25 CD4+ T cell epitope from Mtb, to mice induces antigen-specific memory CD4+ T cells that reside long-term in the lungs (TRM) and protect against aerosol infection with Mtb. Recent studies show that these cells express chemokine receptors, including CXCR3 that enable the entry of these cells into the lungs. The first part of this thesis examines how CXCR3 affects the CD4+ TRM response to PR8.p25. Pulmonary administration of the protein-adjuvant vaccine, CysVac2-Advax™, also induces p25-specific CD4+ TRM that provide protection against Mtb. The second part of this thesis compares the genes expressed by p25-specific CD4+ TRM induced by both vaccines with other CD4+ T cell populations to identify transcriptional signatures of tissue residency and differences between the two TRM populations. Following PR8.p25 vaccination, a high proportion of p25-specific CD4+ T cells, including TRM, maintained CXCR3 expression until day 42. Nevertheless, CXCR3 was not essential for entry and retention of vaccine-induced CD4+ TRM in the lungs, although it conferred a competitive advantage for the recruitment of these cells. PR8.p25-induced CD4+ TRM uniquely upregulated TRM markers, chemokine receptors and effector proteins, including the transcription factors Hobit and HIF-1α, compared to other CD4+ T cells. CysVac2-Advax™-induced TRM distinctly upregulated Th17-related genes. Therefore, lung CD4+ TRM share a transcriptional signature that distinguishes them from other CD4+ T cells, but with differences dependent on the type of vaccine. These results further our understanding of tissue residency in lung CD4+ T cells and their protective capabilities and will aid in future efforts to develop more effective TB vaccines