Cross-reactive tissue-resident memory T lymphocytes-concepts, evidence, and open questions

Area of Science:

• Immunology
• Cell Biology
• Systems Biology

Background:

• Tissue-resident memory T (Trm) cells are crucial for frontline immune surveillance in peripheral tissues and contribute to lasting systemic immunity.
• A key characteristic of Trm cells is their T cell receptor (TCR) cross-reactivity, enabling recognition of multiple antigens beyond their primary target.

Purpose of the Study:

• To review the dual roles of cross-reactive Trm cells in mediating protection and potentially causing autoimmune pathology.
• To explore the developmental origins, tissue distribution, and functions of Trm cells.
• To examine the mechanistic basis of TCR cross-reactivity in Trm cells compared to circulating memory T cells.

Main Methods:

• Synthesis of current knowledge on Trm cell biology and TCR cross-reactivity.
• Analysis of tissue-specific signals, cytokine milieus, and epigenetic modifications shaping Trm cell responses.
• Discussion of therapeutic strategies targeting Trm cell cross-reactivity.

Main Results:

• Cross-reactive Trm cells can provide broad protection against infections and cancers.
• Trm cell cross-reactivity can also precipitate or exacerbate autoimmune diseases.
• Tissue-specific factors and epigenetic changes significantly influence Trm cell functional avidity and antigenic breadth.

Conclusions:

• Trm cells act as potent immune sentinels, with their TCR cross-reactivity offering broad protective immunity.
• Understanding the precise mechanisms governing Trm cell cross-reactivity is essential for developing effective immunotherapies for cancer and infections.
• Harnessing protective Trm cell functions while mitigating autoimmune risks is critical for future therapeutic applications.