CXCR3 Signaling Is Required for Restricted Homing of Parenteral Tuberculosis Vaccine–Induced T Cells to Both the Lung Parenchyma and Airway

Abstract

Although most novel tuberculosis (TB) vaccines are designed for delivery via the muscle or skin for enhanced protection in the lung, it has remained poorly understood whether systemic vaccine-induced memory T cells can readily home to the lung mucosa prior to and shortly after pathogen exposure. We have investigated this issue by using a model of parenteral TB immunization and intravascular immunostaining. We find that systemically induced memory T cells are restricted to the blood vessels in the lung, unable to populate either the lung parenchymal tissue or the airway under homeostatic conditions. We further find that after pulmonary TB infection, it still takes many days before such T cells can enter the lung parenchymal tissue and airway. We have identified the acquisition of CXCR3 expression by circulating T cells to be critical for their entry to these lung mucosal compartments. Our findings offer new insights into mucosal T cell biology and have important implications in vaccine strategies against pulmonary TB and other intracellular infections in the lung.

Enhanced protection conferred by mucosal BCG vaccination associates with presence of antigen-specific lung tissue-resident PD-1+ KLRG1− CD4+ T cells

“…We also report that CXCR3 expression was present only on lung parenchymal CD4 + T cells following mucosal BCG vaccination, and that expression of this marker was highest on PD-1 + KLRG1 − lung parenchymal cells. This contrasts with recent studies 24,44 which describe induction of antigen-specific T cells expressing CXCR3 in the lung vasculature. However, these studies used systemic immunisation with a subunit or viral-vectored TB vaccine rather than BCG, and are therefore not directly comparable.…”

“…Mucosal, but not systemic BCG, induced antigen-specific CD4 + T cells in the broncho-alveolar space. In agreement with this finding, several studies have demonstrated that TB vaccines delivered to the lung mucosa are able to elicit a T cell response within the airway lumen and restrict replication of M. tb in the first week following infection [44][45][46][47][48][49][50][51] . The data presented here, combined with these reports, indicate that airway luminal T cells may be able to provide a first line of defence against M. tb infection and should be considered as a target population when designing new vaccination regimes 49 .…”

“…These markers have been investigated in the context of TB vaccination and M. tb infection 24,25,29,44 , but no data are published on their expression following mucosal delivery of BCG, utilising the intravascular staining technique to definitively identify tissueresident cells.…”

Tissue-resident memory CD8 T-cell responses elicited by a single injection of a multi-target COVID-19 vaccine

“…Furthermore, the CXCR3 chemokine receptor have been reported to be expressed on human lung T-cells and demonstrated to play a significant roles in T-cell homing to the lung parenchyma and ariway since CXCR3 inhibition prevents airway immune responses and vaccine-induced T cell entry to the lung mucosal compartments [75][76][77][78][79] . Here we showed that, as previously observed with our MEMOPI ® -based neoepitope cancer vaccine approach, several peptides induced viral-specific CD8 T cells expressing the E (CD103) and α1 (CD49a) integrins and the CD44 memory marker, altogether characteristic of Trm.…”

Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8+T cells

“…Here we showed that metformin-treatment resulted in an increased (i) elicitation of Ag-specific CD8 + TCM in the tissues of BCG-vaccinated mice, (ii) TNFa secreting Ag-specific CD8 + TCM cells in the tissues of BCGvaccinated Mtb-challenged mice, and (iii) protection of BCG-immunized mice and guinea pig against Mtb challenge. Importantly, expression of CXCR3 by TB vaccine-specific CD8 + T cells is needed for their homing to the lung mucosa 62 . This raises the possibility of the presence of metformin-educated CD8 + T cells in different anatomical location within lung parenchyma, which is responsible for enhanced protective immunity.…”