Lymph nodes serve to bring together antigens delivered by afferent lymph originating in draining tissues to meet lymphocytes recruited from the blood circulation [1]. In addition to antigens and antigen-bearing cells, afferent lymph carries cytokines, lipids, and metabolites that inform the immune system about the tissue state and have the potential to directly and indirectly modulate the antigen-specific T and B cell responses in lymph nodes. In autoimmune diseases, these non-antigenic immune-modifying molecules from diseased tissue could impact the magnitude or other characteristics of autoimmune responses generated in lymph nodes. An example where such impact may be especially relevant is in the autoimmune disease, systemic lupus erythematosus (SLE), a disease characterized by autoantibodies that accumulate with immune cells in target organs, such as kidneys, skin, and brain, to promote tissue inflammation and injury 2, 3, 4. In SLE, patients are photosensitive, where sun exposure to the skin can precipitate a systemic immune response, leading to disease flares, raising blood autoantibody levels, and worsening end organ disease 5, 6. The exact relationship between ultraviolet radiation (UVR) and autoantibody responses is not well understood, but the majority of lupus patients show cutaneous photosensitivity where they develop inflammatory skin lesions after UVR exposure 6, 7. Lupus keratinocytes are more prone to dying upon UVR exposure, and this process could supply nuclear constituents that drive the generation of autoantibodies to nucleic acids and associated binding proteins that are characteristic of lupus 2, 3, 8. Beyond antigen, however, what other signals are being sent from photosensitive skin to draining lymph nodes that modify the antigen-specific responses, and what cells are these signals acting on in lymph nodes to modulate immunity? Understanding the nature of these signals and the relevant cellular recipients of these signals can help to understand how T and B cell responses are regulated and perhaps why UVR is immune suppressive in healthy organisms but apparently not so in SLE. Here, we discuss recent studies that illustrate the array of molecular mediators generated in perturbed tissue that can reach draining lymph nodes and highlight the role of the lymph node stromal compartment in receiving afferent lymph signals to shape immune responses.