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

Abstract

BCG, the only vaccine licensed against tuberculosis, demonstrates variable efficacy in humans. Recent preclinical studies highlight the potential for mucosal BCG vaccination to improve protection. Lung tissue-resident memory T cells reside within the parenchyma, potentially playing an important role in protective immunity to tuberculosis. We hypothesised that mucosal BCG vaccination may enhance generation of lung tissue-resident T cells, affording improved protection against Mycobacterium tuberculosis. In a mouse model, mucosal intranasal (IN) BCG vaccination conferred superior protection in the lungs compared to the systemic intradermal (ID) route. Intravascular staining allowed discrimination of lung tissue-resident CD4 + T cells from those in the lung vasculature, revealing that mucosal vaccination resulted in an increased frequency of antigen-specific tissue-resident CD4 + T cells compared to systemic vaccination. Tissue-resident CD4 + T cells induced by mucosal BCG displayed enhanced proliferative capacity compared to lung vascular and splenic CD4 + T cells. Only mucosal BCG induced antigen-specific tissue-resident T cells expressing a PD-1 + KLRG1 − cell-surface phenotype. These cells constitute a BCG-induced population which may be responsible for the enhanced protection observed with IN vaccination. We demonstrate that mucosal BCG vaccination significantly improves protection over systemic BCG and this correlates with a novel population of BCG-induced lung tissue-resident CD4 + T cells.

Mucosal delivery of a multistage subunit vaccine promotes development of lung-resident memory T cells and affords interleukin-17-dependant protection against pulmonary tuberculosis

“…This may be particularly detrimental in the case of M. tuberculosis infection, where priming and recruitment of effector T lymphocytes to the lungs is delayed, allowing unchecked growth of the organism [24,25]. For this reason, mucosal vaccination has been of interest in the field of TB vaccines, with pulmonary delivery of BCG [14,26], live recombinant viruses [8,27,28], or protein/adjuvants [29,30] resulting in protective immune responses. When administered to the respiratory mucosa, highly inflammatory adjuvanted vaccines may induce protective immunity, but this is often accompanied by excessive inflammation, mucus accumulation and eosinophilia [31].…”

PD-1 modulating Mycobacterium tuberculosis-specific polarized effector memory T cells response in tuberculosis pleurisy

“…PD‐1‐expressing T cells are highly proliferative, whereas KLRG1 cells exhibit a short lifespan and secrete the cytokines IFN‐γ and TNF‐α. Thus, proliferating PD‐1‐positive cells are not exhausted, but appear to be central to maintaining Ag‐specific effector T cells during chronic M.tb infection . Despite this M.tb infection, a subset of PD‐1 + T cells is maintained within the lung parenchyma during TB.…”

Towards new TB vaccines

“…The pulmonary CD4+ T cell response can be divided into two subsets, one in the lung parenchyma, and one residing within the vasculature [137]. The parenchymal effectors are PD-1 hi /CD69 hi CD4+ T cells, which are highly proliferative, in contrast with the more terminally differentiated KLRG1 hi /T-bet hi CD4+ cells resident in the vasculature [137][138][139][140][141]. These KLRG1 hi cells produce more IFN-ɣ [140] and are the most abundant subset in the lung at the peak of clonal expansion [137]; however, they are very poor at entering the lung parenchyma [142].…”

“…Mucosal BCG vaccination has been shown to confer superior protection in the lungs compared with intradermal BCG in mice [139], and parenteral administration in guinea pigs [187] and macaques [188], associated with greater numbers of T RM and an enhanced proliferative capacity of lung parenchymal CD4+ T cells [139,141]. The superior protection was specific to the lungs, with protection in the spleen equal to that conferred by the intradermal route [139]. CXCR3 expression, key to the recruitment of CD8+ T cells [189], was only found in lung parenchymal CD4+ T cells with mucosal BCG vaccination [139].…”

“…The superior protection was specific to the lungs, with protection in the spleen equal to that conferred by the intradermal route [139]. CXCR3 expression, key to the recruitment of CD8+ T cells [189], was only found in lung parenchymal CD4+ T cells with mucosal BCG vaccination [139]. A recent study in NHPs has demonstrated a superior protective effect of mucosal BCG immunisation compared with intradermal immunisation against low-dose repeated M. tuberculosis infection [190].…”