Divergent molecular networks program functionally distinct CD8⁺ skin-resident memory T cells.

Area of Science:

• Immunology
• Cell Biology
• Dermatology

Background:

• Skin-resident CD8+ T cells comprise distinct subsets, including interferon-γ-producing T_RM1 and IL-17-producing T_RM17 cells, which play differential roles in immune responses.
• The molecular mechanisms governing the tissue residency of these distinct T cell populations in the skin remain largely unknown.

Purpose of the Study:

• To investigate the molecular pathways utilized by T_RM1 and T_RM17 cells for establishing skin tissue residency.
• To determine if common or distinct mechanisms govern the commitment and maintenance of these T cell subsets in the skin.

Main Methods:

• Comparative analysis of gene expression and signaling pathways in isolated T_RM1 and T_RM17 cells.
• Genetic manipulation to assess the role of key transcription factors (T-bet, Hobit, c-Maf) and cytokines (IL-15, IL-7) in T cell residency.
• Targeting specific pathways to evaluate their impact on T_RM17 cell populations.

Main Results:

• T_RM1 cell residency is dependent on a T-bet-Hobit-IL-15 axis.
• T_RM17 cell residency is independent of the T-bet-Hobit-IL-15 axis.
• A distinct ICOS-c-Maf-IL-7 axis governs T_RM17 cell commitment and tissue residency, operating parallel to the Hobit pathway in T_RM1 cells.
• Targeting the ICOS-c-Maf-IL-7 pathway selectively ablates skin T_RM17 cells without affecting T_RM1 cells.

Conclusions:

• Skin-resident T_RM1 and T_RM17 cells establish residency through divergent molecular circuitries.
• The identified distinct pathways provide potential targets for the strategic modulation of local skin immunity.