CD69 Promotes Rapid Activation of Skin-Resident Memory T Cells

Introduction/Rationale: Tissue-Resident Memory T cells (TRMs) are long-lived antigen-specific memory T cells embedded in peripheral tissues post-inflammation or infection. These cells patrol their tissues and mount a very rapid response to antigen re-encounter. The canonical marker for TRMs is CD69, however little is known about the role of CD69 in these cells. CD69 is best known as an early activation marker on T cells, and it is detectable on the cell surface within four hours of TCR stimulation. In the lymph node, CD69 inhibits premature egress of activated cells by binding and internalizing the homing receptor S1PR1. Interestingly, S1PR1 is transcriptionally silent in established TRMs, and by definition TRMs have not been recently activated. This leaves the question of what is the function of CD69 on TRMs?

Methods: Using a vaccinia virus model of TRM induction, we established both OTI and OTI-CD69KO TRMs as well as OTI-CD69f/f and OTI-CD69f/f CreERT2 TRMs. After establishing TRMs, we tested their capacity for reactivation through methods including flow cytometry and ELISA.

Results: We show that antigen-specific CD69KO and CD69f/f CreERT2 TRMs have a reduced capacity for recruiting monocytes into the tissue 3 hours after antigen rechallenge when compared to their littermate controls. Mice bearing CD69KO TRMs also exhibit reduced vascular permeability and fluid influx 1 hour after antigen rechallenge compared to their CD69WT TRM-bearing littermate controls. When co-transferred, CD69KO TRMs express less TNFthan their littermate controls within the same ear.

Conclusion: Taken together these results indicate that CD69 contributes to the reactivation of TRMs and allows TRMs to mount a rapid response to antigen reencounter. This information may be leveraged to fine-tune TRMs in the context of cancer and autoimmunity.