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Lymphocytes in lockdown

The field of tissue immunity has undergone a period of explosive growth over the past two decades. Among the many noteworthy studies, it was those by Gebhardt et al. in 2009 and Masopust et al. in 2010 that catapulted research on tissue-resident memory T (TRM) cells into the mainstream. Together, these studies showcased the existence and importance of memory T cells in tissues and the crucial contribution of TRM cells to local immune protection.

Although earlier studies had demonstrated T cell abundance in tissues and supported the notion of their tissue residency (Klonowski et al., 2004; Clark et al., 2006), the studies by Gebhardt and Masopust definitively showed that antigen-specific CD8+ T cells with a unique phenotype persisted in the skin and intestine after local viral infection. Pivotal was the demonstration that these non-migratory T cells were not simply trapped in the tissue, but were a stand-alone population. Moreover, TRM cells mediated site-specific immune responses upon reinfection with the same pathogen.

One of the game-changing outcomes of these studies was the identification of CD69 and CD103 as TRM cell-associated markers (albeit they are not universal TRM cell markers, as shown in later years). This new-found ability to identify TRM cells spurred a flurry of studies that characterized these cells across a range of different tissues in both humans and mice. Subsequent transcriptomic analyses led to insights into how these tissue-embedded cells differ from those in the circulation and revealed the molecular underpinnings of TRM cell development. Most importantly, we have since learnt the value of TRM cells in mediating local immune surveillance, playing a vital role in preventing infection and the development of solid tumours.

Since the Gebhardt and Masopust studies, there has been a seismic shift in how we, as immunologists, study T cell memory. The result is a collective realization of the importance of studying site-specific immune responses and the need to design vaccines that induce tissue-based immunity for effective protection against infections, from influenza to SARS-CoV-2 (Farber, 2021). Understanding how T cells operate in peripheral tissues is key, and by solely looking at blood-borne immunity, we are missing half the story.


Original articles

  1. Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524–530 (2009)

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  2. Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553–564 (2010)

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Related articles

  1. Klonowski, K. D. et al. Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity 20, 551–562 (2004)

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  2. Clark, R. A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 4431–4439 (2006)

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  3. Farber, D. L. Tissues, not blood, are where immune cells function. Nature 593, 506–509 (2021)

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Correspondence to Laura K. Mackay.

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Mackay, L.K. Lymphocytes in lockdown. Nat Rev Immunol 21, 617 (2021).

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