Contribution of Resident Memory CD8+ T Cells to Protective Immunity Against Respiratory Syncytial Virus and Their Impact on Vaccine Design

Abstract

Worldwide, human respiratory syncytial virus (RSV) is the most common etiological agent for acute lower respiratory tract infections (ALRI). RSV-ALRI is the major cause of hospital admissions in young children, and it can cause in-hospital deaths in children younger than six months old. Therefore, RSV remains one of the pathogens deemed most important for the generation of a vaccine. On the other hand, the effectiveness of a vaccine depends on the development of immunological memory against the pathogenic agent of interest. This memory is achieved by long-lived memory T cells, based on the establishment of an effective immune response to viral infections when subsequent exposures to the pathogen take place. Memory T cells can be classified into three subsets according to their expression of lymphoid homing receptors: central memory cells (T_CM), effector memory cells (T_EM) and resident memory T cells (T_RM). The latter subset consists of cells that are permanently found in non-lymphoid tissues and are capable of recognizing antigens and mounting an effective immune response at those sites. T_RM cells activate both innate and adaptive immune responses, thus establishing a robust and rapid response characterized by the production of large amounts of effector molecules. T_RM cells can also recognize antigenically unrelated pathogens and trigger an innate-like alarm with the recruitment of other immune cells. It is noteworthy that this rapid and effective immune response induced by T_RM cells make these cells an interesting aim in the design of vaccination strategies in order to establish T_RM cell populations to prevent respiratory infectious diseases. Here, we discuss the biogenesis of T_RM cells, their contribution to the resolution of respiratory viral infections and the induction of T_RM cells, which should be considered for the rational design of new vaccines against RSV.

Keywords: human orthopneumovirus; human respiratory syncytial virus; resident memory T cells; respiratory infection; vaccine development.

Figure 1

Steps occurring during the activation and differentiation of T lymphocytes. (a). Antigen Presentation. Activation of T cells requires the assembly of an immunological synapse with APCs, which provides three types of signals: i) interaction between the TCR and a peptide-loaded MHC class I or class II molecule, ii) co-stimulatory molecule signaling and iii) specific cytokines. (b). Proliferation/Differentiation. T cell activation induces T cell proliferation to clonally select and expand antigen-specific T cells. (c). Effector functions, surface markers and some cytokines required for homeostasis [53,54,55,56,57,58] and transcription factors that characterize each subpopulation of memory T cells. Central memory T cells (T_CM) express lymphoid homing markers and circulate through secondary lymphoid organs (SLO). The effector memory T cells (T_EM) lack expression of lymphoid homing markers, but express other migratory receptors with the potential to migrate through non-lymphoid tissues. The third subset of memory T cells, which consists of resident memory T cells (T_RM), stably reside in non-lymphoid tissues and contribute to enhancing innate and adaptive immunity against pathogens.