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Lymph nodes (LNs) function as filter for pathogens and are essential organs for initiating adaptive immunity. Lymphatic migration of myeloid cells to LNs is fundamental in this process as it informs on changes in the tissues. Here, we show that tissue-derived unconventional T cells (UTC) similarly migrate to draining LNs. Because each tissue harbors a distinct spectrum of UTC with specific differentiation states and TCR repertoires, every LN is populated by a distinctive tissue-determined mix of UTC. Functionally, UTC cooperate in interconnected units and shape immune responses that differ between LNs. These findings have potential implications for vaccination and immunotherapy.
