However, strong CD8+ T-cell recall responses have also been demonstrated to cause undesired and sometimes https://www.selleckchem.com/products/fg-4592.html lethal immunopathology in certain circumstances [[9, 10, 16, 31]]. Therefore, rational vaccine design needs to take into account the delicate balance between robust immunity

and lethal CD8+ T-cell-mediated immunopathology. Following LCMV-Arm infection, wild-type mice mount vigorous antiviral CD8+ T-cell responses and clear the virus in a perforin-dependent manner [[40]]. PKO mice fail to clear LCMV-Arm and develop chronic infections [[14]]. Moreover, the requirement for perforin-mediated cytolysis in resistance to primary infection with LCMV is well documented [[41]] and PKO mice are models for FHL [[16-19]], a uniformly fatal disease associated with viral infection in human with mutations in perforin gene [[20, 23-25, 42]]. Thus, perforin Hydroxychloroquine clinical trial deficiency represents an immunocompromised state in which defective antiviral CD8+ T-cell response results

in the establishment of chronic infection [[16]]. Previous work in our laboratory demonstrated that vaccination to generate memory CD8+ T cells can overcome perforin deficiency and provide enhanced resistance against intracellular infection with LM [[27, 30]]. In contrast, vaccination of BALB/c-PKO mice results in accelerated mortality following LCMV infection [[16]]. In this case, vaccination of PKO hosts converts a nonlethal persistent infection into a rapidly fatal disease mediated by CD8+ T cells. To understand why vaccination leads to mortality in the absence of perforin, we analyzed multiple parameters that could potentially contribute to the drastic, and ultimately fatal response Immune system observed. We have shown that vaccination-induced mortality is mediated by massive expansion of

NP118-specific memory CD8+ T cells and the associated aberrant cytokine production in PKO mice. Different vaccine strategies did not alter the outcome as long as the number of NP118-specific memory CD8+ T cells exceeds a certain threshold number. In our adoptive transfer experiments (Fig. 3), we observed that the majority of PKO mice succumbed to LCMV infection if they received at least 8 × 104 NP118-specific CD8+ T cells. Assuming 10% “take” of the transferred number, this result indicated that as few as 8000 NP118-specific CD8+ T cells in the spleen at the time of LCMV infection would be sufficient to cause mortality in these PKO mice. Although we did not observe any mortality in mice that received 8 × 103 NP118-specific memory CD8+ T cells (i.e. 800 memory cells in the spleen, assuming 10% take), we documented severe morbidity as significant weight loss in these mice following LCMV infection (Fig. 3C). Thus, even a small number of NP118-specific memory CD8+ T cells is sufficient to cause immunopathology after LCMV infection of PKO mice.