Exercise and tissue-resident memory T cells: from circulating numbers to spatial immune remodeling

Tissue-resident memory T (T_RM) cells have become a paradigm shift in the field of immunology and have changed our view of local immune surveillance at barrier surfaces. In contrast to circulating memory T cells, T_RM cells are fixed in non-lymphoid organs like lungs, intestine and skin to act as the first line of defense against reinfection and malignant conversion. The finding contradicts the conventional emphasis on exercise immunology on the number of circulating lymphocytes and requires a new conceptual framework of the so-called quantitative to spatial immune remodeling. This review summarizes the current developments in the T_RM cell biology and its relevance to exercise immunology and answer the main question of the review: will endurance training, like a vaccine, elevate the density of both T_RM cells in non-lymphoid tissues and their functional capacity? To begin with, we define the molecular basis of T_RM cells, their differentiation routes, storage processes (CD69, CD103), and tissue-specific diversity. Then, we explore the possible ways in which exercise might be able to change the establishment of T_RM cells and their functions, namely exercise related adrenergic signaling, thermoregulatory shifts, and hemodynamic forces regulating the T cell homing receptor and tissue resident program. The traditional finding of decreased upper respiratory tract infection risk in athletes is reevaluated based on the perspective of increased respiratory mucosal T_RM cell immunity. We then elaborate on the biphasic J-shaped relationship between exercise intensity and immunoprotection, and elucidate how optimal training levels are achieved at lower intensities whereas higher intensities can undermine the level of T_RM cell-mediated immunity. Lastly, we have identified key knowledge gaps and research directions that are needed in the future, namely, the mechanistic analysis of β2-adrenergic receptor signaling in T_RM cell biology, the creation of tissue-specific exercise prescription strategies and the translation of these findings into practice as a way to prevent infections and treat cancer immunotherapy. Incorporating basic immunology with exercise physiology, the review is intended to trigger a paradigm shift in exercise immunology shifting away the circulating numbers toward the spatially-resolved insight of how exercise alters the immune picture of the tissues.