Recent studies have characterized populations of memory CD8⁺ T cells that do not recirculate through the blood but are, instead, retained in nonlymphoid tissues. Such CD8⁺ tissue resident memory T cells (T_RM) are critical for pathogen control at barrier sites. Identifying T_RM and defining the basis for their tissue residency is therefore of considerable importance for understanding protective immunity and improved vaccine design. Expression of the molecule CD69 is widely used as a definitive marker for T_RM, yet it is unclear whether CD69 is universally required for producing or retaining T_RM. Using multiple mouse models of acute immunization, we found that the functional requirement for CD69 was highly variable, depending on the tissue examined, playing no detectable role in generation of T_RM at some sites (such as the small intestine), whereas CD69 was critical for establishing resident cells in the kidney. Likewise, forced expression of CD69 (but not expression of a CD69 mutant unable to bind the egress factor S1PR1) promoted CD8⁺ T_RM generation in the kidney but not in other tissues. Our findings indicate that the functional relevance of CD69 in generation and maintenance of CD8⁺ T_RM varies considerably, chiefly dependent on the specific nonlymphoid tissue studied. Together with previous reports that suggest uncoupling of CD69 expression and tissue residency, these findings prompt caution in reliance on CD69 expression as a consistent marker of CD8⁺ T_RM. Key Points CD69 is not required for the establishment of CD8⁺ T_RM in every nonlymphoid tissue. In the kidney, CD69 is required for CD8⁺ T_RM regardless of immunization approach. CD69 deficiency prevents generation of KLF2^low T_RM in the kidney.

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