Tissue-resident memory T (T
) cells were originally identified as a tissue-sequestered population of memory T cells that show lifelong persistence in non-lymphoid organs. That definition has slowly ...evolved with the documentation of T
cells having variable terms of tissue residency combined with a capacity to return to the wider circulation. Nonetheless, reductionist experiments have identified an archetypical population of T
cells showing intrinsic permanent residency in a wide range of non-lymphoid organs, with one notable exception: the lungs. Despite the fact that memory T cells generated during a respiratory infection are maintained in the circulation, local T
cell numbers in the lung decline concomitantly with a decay in T cell-mediated protection. This Perspective describes the mechanisms that underpin long-term T cell lodgement in non-lymphoid tissues and explains why residency is transient for select T
cell subsets. In doing so, it highlights the unusual nature of memory T cell egress from the lungs and speculates on the broader disease implications of this process, especially during infection with SARS-CoV-2.
T cell immunity is often defined in terms of memory lymphocytes that use the blood to access a range of organs. T cells are involved in two patterns of recirculation. In one, the cells shuttle back ...and forth between blood and secondary lymphoid organs, whereas in the second, memory cells recirculate between blood and nonlymphoid tissues. The latter is a means by which blood T cells control peripheral infection. It is now clear that there exists a distinct memory T cell subset that is absent from blood but found within nonlymphoid tissues. These nonrecirculating tissue-resident memory T (TRM) cells develop within peripheral compartments and never spread beyond their point of lodgement. This review examines fixed immune surveillance by TRM cells, highlighting features that make them potent controllers of infection in nonlymphoid tissues. These features provide clues about TRM cell specialization, such as their ability to deal with sequestered, persisting infections confined to peripheral compartments.
Tissue-resident memory T (Trm) cells contribute to local immune protection in non-lymphoid tissues such as skin and mucosa, but little is known about their transcriptional regulation. Here we showed ...that CD8+CD103+ Trm cells, independent of circulating memory T cells, were sufficient for protection against infection and described molecular elements that were crucial for their development in skin and lung. We demonstrated that the T-box transcription factors (TFs) Eomes and T-bet combined to control CD8+CD103+ Trm cell formation, such that their coordinate downregulation was crucial for TGF-β cytokine signaling. TGF-β signaling, in turn, resulted in reciprocal T-box TF downregulation. However, whereas extinguishment of Eomes was necessary for CD8+CD103+ Trm cell development, residual T-bet expression maintained cell surface interleukin-15 (IL-15) receptor β-chain (CD122) expression and thus IL-15 responsiveness. These findings indicate that the T-box TFs control the two cytokines, TGF-β and IL-15, which are pivotal for CD8+CD103+ Trm cell development and survival.
•CD8+CD103+ Trm cells protect against infection in the absence of circulating memory•T-box transcription factor downregulation drives CD8+CD103+ Trm cell development•TGF-β and the T-box transcription factors show reciprocal downregulation•Residual T-bet expression is required for IL-15-mediated CD8+CD103+ Trm cell survival
Molecular events that regulate Trm cell formation remain poorly defined. Mackay and colleagues demonstrate that a complex interplay between Eomes and T-bet underpins CD8+CD103+ Trm cell formation. Although both T-box transcription factors must be downregulated, Eomes must be completely extinguished, whereas residual T-bet expression is essential for IL-15-mediated long-term survival.
The skin is a highly complex organ interspersed with a variety of smaller organ-like structures and a plethora of cell types that together perform essential functions such as physical sensing, ...temperature control, barrier maintenance and immunity. In this Review, we outline many of the innate and adaptive immune cell types associated with the skin, focusing on the steady state in mice and men, and include a broad update of dendritic cell function and T cell surveillance.
Tissues such as the skin and mucosae are frequently exposed to microbial pathogens. Infectious agents must be quickly and efficiently controlled by our immune system, but the low frequency of naive T ...cells specific for any one pathogen means dependence on primary responses initiated in draining lymph nodes, often allowing time for serious infection to develop. These responses imprint effectors with the capacity to home to infected tissues; this process, combined with inflammatory signals, ensures the effective targeting of primary immunity. Upon vaccination or previous pathogen exposure, increased pathogen-specific T cell numbers together with altered migratory patterns of memory T cells can greatly improve immune efficacy, ensuring infections are prevented or at least remain subclinical. Until recently, memory T cell populations were considered to comprise central memory T cells (TCM), which are restricted to the secondary lymphoid tissues and blood, and effector memory T cells (TEM), which broadly migrate between peripheral tissues, the blood, and the spleen. Here we review evidence for these two memory populations, highlight a relatively new player, the tissue-resident memory T cell (TRM), and emphasize the potential differences between the migratory patterns of CD4(+) and CD8(+) T cells. This new understanding raises important considerations for vaccine design and for the measurement of immune parameters critical to the control of infectious disease, autoimmunity, and cancer.
Barrier tissues such as the skin contain various populations of immune cells that contribute to protection from infections. These include recently identified tissue-resident memory T cells (T RM). In ...the skin, these memory CD8 ⁺ T cells reside in the epidermis after being recruited to this site by infection or inflammation. In this study, we demonstrate prolonged persistence of epidermal T RM preferentially at the site of prior infection despite sustained migration. Computational simulation of T RM migration within the skin over long periods revealed that the slow rate of random migration effectively constrains these memory cells within the region of skin in which they form. Notably, formation of T RM involved a concomitant local reduction in dendritic epidermal γδ T-cell numbers in the epidermis, indicating that these populations persist in mutual exclusion and may compete for local survival signals. Accordingly, we show that expression of the aryl hydrocarbon receptor, a transcription factor important for dendritic epidermal γδ T-cell maintenance in skin, also contributes to the persistence of skin T RM. Together, these data suggest that skin tissue-resident memory T cells persist within a tightly regulated epidermal T-cell niche.
Tissue-resident memory T cells provide local immune protection in barrier tissues, such as skin and mucosa. However, the molecular mechanisms controlling effector T cell retention and subsequent ...memory formation in those locations are not fully understood. In this study, we analyzed the role of CD69, an early leukocyte activation marker, in regulating effector T cell egress from peripheral tissues. We provide evidence that CD69 surface expression by skin-infiltrating CD8 T cells can be regulated at multiple levels, including local Ag stimulation and signaling through type I IFNRs, and it coincides with the transcriptional downregulation of the sphingosine-1-phosphate receptor S1P1. Importantly, we demonstrate that expression of CD69, by interfering with sphingosine-1-phosphate receptor function, is a critical determinant of prolonged T cell retention and local memory formation. Our results define an important step in the generation of long-lived adaptive immune memory at body surfaces.
Although circulating memory T cells provide enhanced protection against pathogen challenge, they often fail to do so if infection is localized to peripheral or extralymphoid compartments. In those ...cases, it is T cells already resident at the site of virus challenge that offer superior immune protection. These tissue-resident memory T (TRM) cells are identified by their expression of the α-chain from the integrin αE(CD103)β7, and can exist in disequilibrium with the blood, remaining in the local environment long after peripheral infections subside. In this study, we demonstrate that long-lived intraepithelial CD103+CD8+ TRM cells can be generated in the absence of in situ antigen recognition. Local inflammation in skin and mucosa alone resulted in enhanced recruitment of effector populations and their conversion to the TRM phenotype. The CD8+ TRM cells lodged in these barrier tissues provided long-lived protection against local challenge with herpes simplex virus in skin and vagina challenge models, and were clearly superior to the circulating memory T-cell cohort. The results demonstrate that peripheral TRM cells can be generated and survive in the absence of local antigen presentation and provide a powerful means of achieving immune protection against peripheral infection.
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