Assessing the Generation of Tissue Resident Memory T Cells by Vaccines

Vaccines are one of the most effective and inexpensive public health interventions after clean water and hand hygiene. They have been instrumental in the elimination of polio in the United States and in the eradication of smallpox worldwide. Vaccine immunogenicity has historically been judged by antibody titres, which are often relied upon as a surrogate marker of protection. This is based on their proven clinical association with protective immunity and the ease, speed and reproducibility of such assessments across laboratories. Antibody assays require small volumes of blood, remain stable over time with banked sera and are readily commercialized. Efforts to understand the role of T cell immunity elicited by vaccines have generally focused on T cells circulating in peripheral blood, and these studies are technically much more challenging and involve many more variables. In the present Review, we focus on whether a recently described subset of memory T cells — namely tissue resident memory T cells (T_RM cells) — may also have a key role in vaccine-induced protective immunity.

Although sampling blood provides a useful approximation of systemic humoral immunity, the recent appreciation that most memory T cells reside in peripheral tissues highlights the need for better characterization of immune cells within tissues and organs. There is a greater awareness of the subsets of memory T cells that do not recirculate, namely T_RM cells, and a growing appreciation of their role in immune homeostasis and protection. T_RM cells and other T cells in tissues greatly outnumber circulating T cells; for example, each square centimetre of human skin is home to one million T cells, and phenotypical analyses suggest that more than 50% of these are T_RM cells, making skin T_RM cells twice as abundant as circulating memory T cells in the peripheral blood. T_RM cells and other tissue T cells also provide rapid and potent recall responses in the skin and mucosal tissues. However, obtaining useable numbers of T cells from tissue in patients is not straightforward and most methods are not available outside a handful of academic laboratories, posing challenges for studies in humans. Much of what we know about T_RM cells has come from mouse models, which for many reasons are only partially translatable to human biology. In this Review, we first highlight some key features in the biology of T_RM cells. We then discuss how to enhance their role in vaccine-induced immune protection, and propose that a focus on tissue T cells, including T_RM cells, should be more routinely integrated into early-stage vaccine research and development.

T_RM cells were initially described, somewhat provocatively, in the setting of systemic viral infection. Although it was already known that effector memory T cells (T_EM cells) are found in peripheral tissues, T_RM cells are a distinct subset of memory T cells characterized by long-term residency in peripheral non-lymphoid tissues. T_RM cell populations from different tissue sites have been shown to share a core gene expression profile, and to have tissue-specific differences in gene expression. Other memory T cells that are found in the extravascular space of tissue are heterogeneous; in human skin, T cells with relatively shorter and longer ‘dwell’ times in skin have been identified. These non-T_RM cell populations eventually exit the skin and enter peripheral blood. This is in contrast to almost all T_RM cells, which remain as long-term residents within the tissue. Both CD4 and CD8 T⁺⁺_RM cell populations have been described in skin, with CD8 T⁺_RM cells associated with antiviral immunity and CD4 T⁺_RM cells more closely linked with immunity to bacteria and fungi. A comparison of the transcriptional profiles of resident and circulating T cells from multiple tissues demonstrated that T_RM cells from sites across the body (for example, lungs, skin and gut) have a core conserved transcriptional signature that distinguishes them from both T_EM cells and central memory T cells (T_CM cells), although the markers originally used to discriminate these cells from each other nearly 20 years ago have limitations. The transcriptomes of T_EM cells and T_CM cells reveal that these cell types more closely resemble each other than they do T_RM cells. Their anatomic location allows T_RM cells to act as immunological sentries, functioning as ‘alarm’ cells that are programmed to persist in tissues and elicit a rapid recall immune response upon antigen encounter. Fundamentally, they have been shown to provide enhanced immunity against re-infection and to accelerate pathogen clearance.