Role of Lymphotoxin in T-Cell Responses during an Acute Viral Infection

The importance of lymphotoxin (LT ) in lymphoid organogenesis is well established. Although LT has been implicated in the pathogenesis of T-cell-mediated immunopathologies, the requirement for LT in T-cell activation and effector function in vivo is not well understood. To determine the role of LT in T-cell activation in vivo, we compared the generation of antigen-specific T-cell responses between wild type ( / ) and LT deficient (LT / ) mice during an acute infection with lymphocytic choriomeningitis virus (LCMV). Our studies showed that LCMV-infected LT / mice had a profound impairment in the activation and expansion of virus-specific CD8 T cells in the spleen, as determined by cytotoxicity assays, intracellular staining for gamma interferon, and staining with major histocompatibility complex class I tetramers. Further, the nonlymphoid organs of LT / mice also contained substantially lower number of LCMV-specific CD8 T cells than those of / mice. Greatly reduced virus-specific CD8 T-cell responses in LT / mice led to a defect in LCMV clearance from the tissues. In comparison to that in / mice, the activation of LCMV-specific CD4 T cells was also significantly attenuated in LT / mice. Adoptive transfer experiments were conducted to determine if abnormal lymphoid architecture in LT / mice caused the impairment in the activation of LCMV-specific T-cell responses. Upon adoptive transfer into / mice, the activation and expansion of LCMV-specific LT / T cells were restored to levels comparable to those of / T cells. In a reciprocal cell transfer experiment, activation of / T cells was significantly reduced upon transfer into LT / mice. These results showed that impairment in the activation of LCMV-specific T cells in LT / mice may be due to abnormal lymphoid architecture and not to an intrinsic defect in LT / T cells.