Acute major tissue injury induces immune dysregulation that is characterized by the development of systemic sterile inflammation and an increased risk for opportunistic infections. Although the contribution of the innate immune system has been examined in detail, research on the impact of acute sterile tissue damage on the T cell compartment remains limited. In the current study, we used a clinically relevant mouse model for traumatic skeletal muscle injury to investigate the impact of sterile tissue damage on diverse subpopulations of CD4⁺ Th and CD8⁺ cytotoxic T cells in systemic and local lymphoid organs. For the first time, to our knowledge, we provide evidence that injury selectively induced the expression of the activation marker CD69 on naive and central/virtual memory CD8⁺ T cells in the lymph nodes but not in the spleen of male mice. CD4⁺ Th cells remained unaffected in both organs. The activation of CD8⁺ T cells was dependent on signaling through TLR4. Within a few hours, injury triggered the expression of IL-12 in the lymph nodes in a TLR4-dependent manner. Blocking of IL-12 prevented the activation of naive and central memory CD8⁺ T cells after injury. Thus, early after traumatic tissue damage, TLR4 transactivates naive and central/virtual memory CD8⁺ T cells through innate cytokines in local lymph nodes, where they might modulate forthcoming local immune responses.