TRM cells

TRM is the acronym for: tissue resident memory. These are tissue-resident CD4+ memory T cells, a special T cell type of immunological memory that provides local protection against infections (and tumors). Tissue-resident T cells (TRM cells) arise as specialized memory cells as a result of infections. After the infection has subsided, they remain in the affected organs and take over the defense against microbes on the front line. They are also a central component of immunity after vaccination.

Memory T cells are mainly divided into two subgroups: central memory T cells (TCMs) and effector memory T cells (TEMs) (Sallusto F et al. 1999). TCMs highly express the receptors CCR7 and CD62L for colonization in secondary lymphoid organs and circulate between blood and secondary lymphoid organs (von Andrian UH et al. 2000).
In contrast to TCMs and TEMs, TRMs (Tissue Resident Memory T Cells) remain permanently in peripheral tissues, including the skin and intestine. They are therefore not recirculated via the bloodstream. In peripheral tissues, they act as alarm sensor cells or cytotoxic cells and mediate a local immune response to re-emerging pathogens (Mueller SN et al. 2016). Thus, TRMs play a major role in intestinal and skin immunity (Park SL et al. 2019; Wu HJ et al. 2018). TRMs persist in the skin over a long period of time. They can be reactivated in the event of a new infection with the same antigen.

Understanding the function ofTRM cells in intestinal immunity is crucial for the development of new therapies and vaccines targeting TRMs. IntestinalTRMs are phenotypically distinct from TEMs. CD69 and CD103 are the two most important cell surface markers identified forTRMs. The lectin CD69, a marker for early T cell activation, is re-expressed in intestinalTRMs and can be used to distinguish TRMs from circulating ^CD4+Tlymphocytes. Another marker for TRMs is CD103 (αE integrin). It is expressed by most CD8+ cells and few ^CD4+ cells in the intestine. ^{CD8+CD103- TRMs} express high levels of beta 2 integrin.

^{CD8+CD69+CD103+TRM}cells are the well-characterized subtype that develops in the epidermis. Local mediators such as interleukin -15 and transforming growth factor(TGF)-beta are required for the formation of a long-livedTRM cell population in the skin. TRM cells of the skin attack virus-infected cells, proliferate in situ in response to local antigens and do not migrate out of the epidermis. The secondaryTRM cell populations originate from pre-existingTRM cells and newly recruitedTRM precursors from the bloodstream.

In addition to microbial pathogens, local application of chemical allergens to the skin leads to delayed hypersensitivity and increases the number of antigen-specific CD8+TRM cells at the site of attack. TRM cells of the skin are also involved in pathological conditions, including vitiligo, psoriasis, fixed drug reactionuand cutaneous T-cell lymphoma (CTCL). Apparently, the functions of these TRM cells vary depending on the pathology.

Psoriasis plaques often reappear in the originally affected areas. When the skin of psoriasis patients is stimulated, the CD8+CD103+CD49a TRM cells in the epidermis appear to be reactivated and initiate IL-17A production.

In vitiligo, autoreactive ^{CD8+CD103+CD49a+TRM}cells secreting interferon-gamma are detectable in lesional skin.

In the fixed drug reaction, intraepidermal ^CD8+TRMcells with an effector memory phenotype are also detectable lesionally. They apparently play an important role in the development of localized tissue damage.

In cutaneous T-cell lymphomas, there is a clonal expansion of transformedTRM cells in the skin. It is assumed that the histological picture of so-called "pagetoid reticulosis" is caused by epidermal CD8+TRM cells.

Compared to TRMs in other tissues, TRMs persist in the skin for years and express skin-specific homing antigens such as cutaneous lymphocyte antigen (CLA) and CCR8. In addition, certain skin retention markers, including CD103 and CD69, are upregulated. Mouse models have shown that TRM require interleukin-15 and TGF-beta for their differentiation in the skin.

The complex role of TRM cells in autoimmune skin diseases is currently being investigated. However, it is clear that TRMs play an important role in the reactivation of the disease and in disease flare-ups. This finding is also likely to have therapeutic consequences.

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