Ultraviolet radiation (UVR) is primarily recognized for its detrimental effects such as cancerogenesis, skin aging, eye damage, and autoimmune disorders. With exception of ultraviolet B (UVB) requirement in the production of vitamin D3, the positive role of UVR in modulation of homeostasis is underappreciated. Skin exposure to UVR triggers local responses secondary to the induction of chemical, hormonal, immune, and neural signals that are defined by the chromophores and extent of UVR penetration into skin compartments. These responses are not random and are coordinated by the cutaneous neuro-immuno-endocrine system, which counteracts the action of external stressors and accommodates local homeostasis to the changing environment. The UVR induces electrical, chemical, and biological signals to be sent to the brain, endocrine and immune systems, as well as other central organs, which in concert regulate body homeostasis. To achieve its central homeostatic goal, the UVR-induced signals are precisely computed locally with transmission through nerves or humoral signals release into the circulation to activate and/or modulate coordinating central centers or organs. Such modulatory effects will be dependent on UVA and UVB wavelengths. This leads to immunosuppression, the activation of brain and endocrine coordinating centers, and the modification of different organ functions. Therefore, it is imperative to understand the underlying mechanisms of UVR electromagnetic energy penetration deep into the body, with its impact on the brain and internal organs. Photo-neuro-immuno-endocrinology can offer novel therapeutic approaches in addiction and mood disorders; autoimmune, neurodegenerative, and chronic pain-generating disorders; or pathologies involving endocrine, cardiovascular, gastrointestinal, or reproductive systems.

Regulating the differentiation and persistence of encephalitogenic T cells is critical for the development of experimental autoimmune encephalomyelitis (EAE). We reported recently that CD5 has an engagement-dependent prosurvival activity in T cells that played a direct role in the induction and progression EAE. We predicted that CD5 regulates T cell apoptosis/survival through the activation of CK2, a prosurvival serine/threonine kinase that associates with the receptor. To test this hypothesis, we generated mice expressing CD5 with the inability to bind and activate CK2 and assessed their susceptibility to EAE. We found mice deficient in CD5-CK2 signaling pathway were mostly resistant to the development of EAE. Resistance to EAE was associated with a dramatic decrease in a population of effector infiltrating Th cells that coexpress IFN-γ and IL-17 and, to a lesser extent, cells that express IFN-γ or IL-17 in draining lymph nodes and spinal cords. We further show that T cells deficient in CD5-CK2 signaling hyperproliferate following primary stimulation; however, following restimulation, they rapidly develop nonresponsiveness and exhibit elevated activation-induced cell death. Our results provide a direct role for CD5-CK2 pathway in T cell activation and persistence of effector T cells in neuroinflammatory disease. This study predicts that targeting of IFN-γ⁺/IL-17⁺ infiltrating Th cells will be useful for the treatment of multiple sclerosis and other systemic autoimmune diseases.

The transmembrane protein CD5, expressed on all T cells and the B1 subset of B cells, modulates antigen receptor-mediated activation. We used the yeast two-hybrid system to identify proteins that interact with its cytoplasmic domain and play a role in CD5 proximal signaling events. We found that the beta subunit of the serine/threonine kinase casein kinase 2 (CK2) interacts specifically with the cytoplasmic domain of CD5. Co-immunoprecipitation experiments showed activation-independent association of CK2 with CD5 in human and murine B and T cell lines and murine splenocytes. The interaction of CK2 holoenzyme with CD5 is mediated by the amino terminus of the regulatory subunit beta. CK2 binds and phosphorylates CD5 at the CK2 motifs flanked by Ser459 and Ser461. Cross-linking of CD5 leads to the activation of CD5-associated CK2 in a murine B-lymphoma cell line and a human T-leukemia cell line and is independent of net recruitment of CK2 to CD5. In contrast, CK2 is not activated following cross-linking of the B cell receptor complex or the T cell receptor complex. This direct regulation of CK2 by a cell surface receptor provides a novel pathway for control of cell activation that could play a significant role in regulation of CD5-dependent antigen receptor activation in T and B cells.