Incomplete Memories: The Natural Suppression of Tissue-Resident Memory CD8 T Cells in the Lung

Abstract

The yearly, cyclic impact of viruses like influenza on human health and the economy is due to the high rates of mutation of traditional antibody targets, which negate any preexisting humoral immunity. However, the seasonality of influenza infections can equally be attributed to an absent or defective memory CD8 T cell response since the epitopes recognized by these cells are derived from essential virus proteins that mutate infrequently. Experiments in mouse models show that protection from heterologous influenza infection is temporally limited and conferred by a population of tissue-resident memory (TRM) cells residing in the lung and lung airways. TRM are elicited by a diverse set of pathogens penetrating mucosal barriers and broadly identified by extravascular staining and expression of the activation and adhesion molecules CD69 and CD103. Interestingly, lung TRM fail to express these molecules, which could limit tissue retention, resulting in airway expulsion or death with concomitant loss of heterologous protection. Here, we make the case that respiratory infections uniquely evoke a form of natural immunosuppression whereby specific cytokines and cell–cell interactions negatively impact memory cell programming and differentiation. Respiratory memory is not only short-lived but most of the memory cells in the lung parenchyma may not be bona fide TRM. Given the quantity of microbes humans inhale over a lifetime, limiting cellular residence could be a mechanism employed by the respiratory tract to preserve organismal vitality. Therefore, successful efforts to improve respiratory immunity must carefully and selectively breach these inherent tissue barriers.

Mucosal vaccine adjuvant cyclic di-GMP differentiates lung moDCs into Bcl6+and Bcl6−mature moDCs to induce lung memory CD4+THcells and lung TFHcells respectively

“…We used lung ex vivo recall assay to 401 determine the total lung CD4 + memory T cells, including memory TH1, TH2, and TH17 cells 402 induced by immunization. We reasoned that though the lung memory TH responses are mainly 403 from lung CD4 + TRM cells, TEM cells or other unknown memory CD4 T cells in the lung may also 404 contribute to the total lung memory TH responses (Reagin and Klonowski, 2018). Furthermore, 405 growing evidence suggest that TRM cells, even at the same tissue site, e.g.…”

Memory T Cell Dynamics in the Lung during Influenza Virus Infection

“…A major obstacle for the development of an intranasal vaccine that evokes lung Trm is that vaccine delivery into the lower airways presents a risk. The lung is a sensitive environment; excessive inflammation elicited by the pulmonary administration of vaccines or inflammatory agents could damage the lung tissue, a situation that could have a negative impact on respiratory health (137).…”

Tissue-Resident Memory T Cells in Mice and Humans: Towards a Quantitative Ecology

“…Although experimental studies have provided valuable insights into longevity in different tissues, the majority measure T RM abundance over time and cannot untangle the contributions of recruitment, self-renewal, and loss. For instance, the rapid loss of influenza-specific T RM in the lung has been attributed to all three components of population longevity: high levels of apoptosis-driven loss, low levels of proliferation, and decreasing recruitment of circulating precursors over time (65,67,73). However, direct quantitative comparisons of the relative roles of each are currently lacking.…”