Modulating CD8⁺ T cell responses in vivo

E. Scott Halstead

doi:10.17918/00000844

CD137 stimulation has been shown to preferentially act to costimulate the proliferation of CD8+ T cells, though its mechanism of action is unclear. We found that in vivo CD137 (4-1BB) stimulation with an agonistic mAb enhanced the primary CD8+ T cell response to influenza type A virus infection in mice. CD137 stimulation increased the frequency and absolute number of CD8+ T cells against influenza virus epitopes and preferentially enhanced the response to nondominant epitopes. Also, CD137 stimulation could substitute for CD28 signaling, as CD137 stimulation was able to restore influenza-specific CD8+ T cell response in CD28-/- mice. CD 137 stimulation continued to support the increased absolute number and frequency of influenza-specific CD8+ T cells late through the contraction phase (day 15), but eventually this effect diminished and by day 20 levels of influenza-specific CD8+ T cells were equivalent in CD137 stimulated and untreated mice. Recall CD8+ T cell responses to influenza virus were in fact inhibited by CD137 stimulation during priming as virus-specific CD8 + T cell frequencies and absolute numbers were decreased following rechallenge with influenza virus. These results indicate that CD137 stimulation enhances primary CD8+ T cell responses but that the memory pool does not reflect this enhancement. Thus, CD137 stimulation may prove important in increasing the primary CD8+ T cell clonal burst, but that enhancement of long-term CD8+ T cell memory will require further manipulations. While CD8+ cytotoxic T lymphocytes (CTL) are important for host defense, they have also been implicated as having an important role in autoimmune rejection phenomena such as type I diabetes, allogeneic transplantation and graft versus host disease. Using structure-based drug design, synthetic peptides that mimic the CD8 [alpha]-chain surface and interfere with CD8 binding to MHC class I have been generated. We examined one such analog, RDY, could inhibit the immunodominant CD8+ T cell response in mice infected with influenza type A virus. Treatment with the RDY analog did significantly reduce expression of the early activation marker CD69 and increased the frequency of "resting" virus-specific CD8+ T cells, thus indicating an inhibition of activation. RDY treatment did not affect the numbers, frequency or effector functions of the virus-specific CTLs. These results suggest that the CD8 peptide mimetic, RDY, can inhibit the activation of virus-specific CD8+ T cells during CD8+ primary immune responses and similar peptide mimetics may serve a role in the treatment of autoimmune disorders. (Abstract shortened by UMI.).

Modulating CD8⁺ T cell responses in vivo

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Modulating CD8⁺ T cell responses in vivo

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