biostudies-literatureUnknown6Santiago-Cruz WCD38 is a transmembrane glycoprotein involved in NAD⁺ metabolism, calcium signaling, and immune cell activation. Its role in the inflammatory response has been studied extensively in innate immune cells; however, its contribution to the activation of memory T lymphocytes under inflammatory conditions is less understood. Additionally, recent studies have shown an age-related increase in the expression of the protein CD38 in various human and murine tissues. Moreover, CD8⁺ bystander T cells have been shown to contribute to inflammation during the aging process. Given the importance of its potential role in age-related pathologies, we examined the effect of CD38 on bystander activation of CD8⁺ memory T cells in aged mice following lipopolysaccharide challenge. CD38-deficient mice exhibited attenuated serum cytokine responses (IL-1β, IL-6, IFN-γ, and IL-10) and a distinct CD8⁺ T cell profile, characterized by a decrease in activated T cells. Wild-type mice displayed a significant expansion of CD69⁺T_CM cells after LPS inoculation, an effect that was absent in CD38-deficient animals. LPS also promoted the expression of CD69 and CD38 in T_EM/EFF subsets. Thus, our findings reveal a CD38-dependent mechanism underlying bystander activation of memory CD8⁺ T cells in aging. Highlighting the potential contribution of CD38 to age-related diseases, such as autoimmunity, and in the face of inflammatory conditions in aged people.Frontiers in aging1701685https://www.ebi.ac.uk/biostudies/studies/S-EPMC12757697biostudies-literatureCD38 promotes LPS-induced innate-like activation and proliferation of CD8<sup>+</sup> T lymphocytes in aged mice.PMC12757697Perez-Lara JCGarcia-Garcia FRodriguez-Alba JCEspinosa EDevarajan PSantiago-Cruz WRomero-Ramirez HfalseCD38 promotes LPS-induced innate-like activation and proliferation of CD8<sup>+</sup> T lymphocytes in aged mice.CD38 is a transmembrane glycoprotein involved in NAD⁺ metabolism, calcium signaling, and immune cell activation. Its role in the inflammatory response has been studied extensively in innate immune cells; however, its contribution to the activation of memory T lymphocytes under inflammatory conditions is less understood. Additionally, recent studies have shown an age-related increase in the expression of the protein CD38 in various human and murine tissues. Moreover, CD8⁺ bystander T cells have been shown to contribute to inflammation during the aging process. Given the importance of its potential role in age-related pathologies, we examined the effect of CD38 on bystander activation of CD8⁺ memory T cells in aged mice following lipopolysaccharide challenge. CD38-deficient mice exhibited attenuated serum cytokine responses (IL-1β, IL-6, IFN-γ, and IL-10) and a distinct CD8⁺ T cell profile, characterized by a decrease in activated T cells. Wild-type mice displayed a significant expansion of CD69⁺T_CM cells after LPS inoculation, an effect that was absent in CD38-deficient animals. LPS also promoted the expression of CD69 and CD38 in T_EM/EFF subsets. Thus, our findings reveal a CD38-dependent mechanism underlying bystander activation of memory CD8⁺ T cells in aging. Highlighting the potential contribution of CD38 to age-related diseases, such as autoimmunity, and in the face of inflammatory conditions in aged people.2025-01-01T00:00:00Z20252026-06-06T10:37:58.829Z2026-05-29T03:12:08.391ZS-EPMC127576974148827510.3389/fragi.2025.1701685