sirolimus and Vaccinia

The induction of functional memory cytotoxic T lymphocytes (CTLs) is a major goal of vaccination against intracellular pathogens. Interleukin (IL)-12 is critical for the generation of memory CTLs, and inhibition of mammalian target of rapamycin (mTOR) by rapamycin can effectively enhance the memory CTL response. Yet, the role of IL-12 in mTOR's regulation of memory CTL is unknown. Here we hypothesized that the immunostimulatory effects of mTOR on memory CTLs requires IL-12 signaling. Our results revealed that rapamycin increased the generation of memory CTLs in vaccinia virus infection, and this enhancement was dependent upon the IL-12 signal. Furthermore, IL-12 receptor deficiency diminished the secondary expansion of rapamycin-regulated memory and resultant secondary memory CTLs were abolished. Rapamycin enhanced IL-12 signaling by upregulating IL-12 receptor β2 expression and signal transducer and activator of transcription factor 4 phosphorylation in CTLs during early infection. In addition, rapamycin continually suppressed T-bet expression in both wild-type and IL-12 receptor knockout CTLs. These results indicate an essential role for IL-12 in the regulation of memory CTLs by mTOR and highlight the importance of considering the interplay between cytokines and adjuvants during vaccine design.

Topics: Adoptive Transfer; Animals; Cell Proliferation; Cells, Cultured; Flow Cytometry; Host-Pathogen Interactions; Immunologic Memory; Immunosuppressive Agents; Interleukin-2; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Receptors, Interleukin-12; Signal Transduction; Sirolimus; STAT4 Transcription Factor; T-Box Domain Proteins; T-Lymphocytes, Cytotoxic; TOR Serine-Threonine Kinases; Vaccinia; Vaccinia virus

Sirolimus is a potent antiproliferative agent used clinically to prevent renal allograft rejection. However, little is known about the effects of maintenance immunosuppressive agents on the immune response to potentially protective vaccines. Here we show that sirolimus paradoxically increases the magnitude and quality of the CD8+ T-cell response to vaccinia vaccination in nonhuman primates, fostering more robust recall responses compared to untreated and tacrolimus-treated controls. Enhancement of both the central and effector memory compartments of the vaccinia-specific CD8+ T-cell response was observed. These data elucidate new mechanistic characteristics of sirolimus and suggest immune applications extending beyond its role as an immunosuppressant.

Topics: Animals; CD8-Positive T-Lymphocytes; Cytokines; Flow Cytometry; Immunologic Memory; Immunosuppressive Agents; Macaca mulatta; Sirolimus; Vaccination; Vaccinia; Vaccinia virus; Viral Vaccines