A Distinct Lung-Interstitium-Resident Memory CD8 + T Cell Subset Confers Enhanced Protection to Lower Respiratory Tract Infection

Abstract

The nature and anatomic location of the protective memory CD8+ T cell subset induced by intranasal vaccination remain poorly understood. We developed a vaccination model to assess the anatomic location of protective memory CD8+ T cells and their role in lower airway infections. Memory CD8+ T cells elicited by local intranasal, but not systemic vaccination with an engineered non-replicative CD8+ T cell-targeted antigen confer enhanced protection to a lethal respiratory viral challenge. This protection depends on a distinct CXCR3LO resident memory CD8+ T cell (Trm) population that preferentially localizes to the pulmonary interstitium. Interstitial Trm —by being positioned close to the mucosa where infection occurs—act before inflammation can recruit circulating memory CD8+ T cells into the lung tissue. This results in a local protective immune response as early as one day post-infection. Hence, vaccine strategies that induce lung interstitial Trm may confer better protection against respiratory pathogens

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…CXCR3 lo T RM cells provide critical protection. 81 An independent investigation also confirms that CXCR3 hi and CXCR3 lo lung CD8 + T cells represent different differentiation stages in response to local inflammation (e.g., IL-12 and IL-15) and occupy distinct niches in the lung. Further, cooperative action from both CXCR3 hi and CXCR3 lo lung T RM s is required for the protection against lethal respiratory VACV challenge 12.…”

Persistence in Temporary Lung Niches: A Survival Strategy of Lung-Resident Memory CD8+T Cells

“…Ultimately, a better understanding of CD8 memory in the lung is essential for the development of safe and effective vaccines capable of generating long-lasting antigen-specific memory CD8 + T cells. Despite a great deal of progress in understanding CD8 + T cell memory in the lung and recent success in generating lung CD8 + T RM cells by vaccination (37,133,139), our identification of specific niches for CD8 + T RM cells in the lung and other data raises a fundamental possibility that lung CD8 + T RM cells are by necessity short lived (e.g., several months). This is primarily due to the lack of preexisting CD8 + T RM niches in the lung and the shortlived nature of these niches.…”

Zymosan by-passes the requirement for pulmonary antigen encounter in lung tissue-resident memory CD8+ T cell development

“…Several vaccination regimes that promote pulmonary CD8 + Trm development have been designed, and these have been shown to effectively limit the severity of respiratory viral infections. 1,3,5,21,[28][29][30] To date, these approaches all rely on local immunisation with a CD8 + T-cell-targeted epitope plus adjuvant. Although pulmonary delivery of antigen is important for vaccineinduced lung Trm development, at present, it is unclear if the adjuvant co-administered with the vaccine antigen also impacts Trm development.…”