CXCR3 Provides a Competitive Advantage for Retention of Mycobacterium tuberculosis-Specific Tissue-Resident Memory T Cells Following a Mucosal Tuberculosis Vaccine

Author:

Armitage Ellis1,Quan Diana1,Flórido Manuela1,Palendira Umaimainthan12,Triccas James A.23,Britton Warwick J.145ORCID

Affiliation:

1. Centenary Institute, The University of Sydney, Sydney, NSW 2006, Australia

2. School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia

3. The University of Sydney Infectious Diseases Institute (Sydney ID), Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia

4. Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia

5. Department of Clinical Immunology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia

Abstract

Mycobacterium tuberculosis is a major human pathogen, and new vaccines are needed to prevent transmission. Mucosal vaccination may confer protection against M. tuberculosis by stimulating tissue-resident memory (TRM) CD4+ T cells in the lungs. The chemokine receptor CXCR3 promotes lung recruitment of T cells, but its role in TRM development is unknown. This study demonstrates the recombinant influenza A virus vaccine PR8.p25, expressing the immunodominant M. tuberculosis T cell epitope p25, induces CXCR3 expression on p25-specific CD4+ T cells in the lungs so that the majority of vaccine-induced CD4+ TRM expresses CXCR3 at 6 weeks. However, CXCR3−/− mice developed equivalent antigen-specific CD4+ T cell responses to wild-type (WT) mice following PR8.p25, and surprisingly retained more p25-specific CD4+ TRM in the lungs than WT mice at 6 weeks. The adoptive transfer of CXCR3−/− and WT P25 T cells into WT mice revealed that the initial recruitment of vaccine-induced CD4+ T cells into the lungs was independent of CXCR3, but by 6 weeks, CXCR3-deficient P25 T cells, and especially CXCR3−/− TRM, were significantly reduced compared to CXCR3-sufficient P25 T cells. Therefore, although CXCR3 was not essential for CD4+ TRM recruitment or retention, it provided a competitive advantage for the induction of M. tuberculosis-specific CD4+ TRM in the lungs following pulmonary immunization.

Funder

the Australian National Health and Medical Research Council

Publisher

MDPI AG

Subject

Pharmacology (medical),Infectious Diseases,Drug Discovery,Pharmacology,Immunology

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