An MHC Class Ib-Restricted CD8+ T Cell Response to Lymphocytic Choriomeningitis Virus

Abstract

Conventional MHC class Ia-restricted CD8+ T cells play a dominant role in the host response to virus infections but recent studies indicate that T cells with specificity for nonclassical MHC class Ib molecules may also participate in host defense. To investigate the potential role of class Ib molecules in anti-viral immune responses, Kb−/−Db−/−CIITA−/− mice lacking expression of MHC class Ia and class II molecules were infected with LCMV. These animals have a large class Ib-selected CD8+ T cell population and they were observed to mediate partial (but incomplete) virus clearance during acute LCMV infection as compared to Kb−/−Db−/−®2M−/− mice that lack expression of both MHC class Ia and class Ib molecules. Infection was associated with expansion of splenic CD8+ T cells and induction of granzyme B and IFN© effector molecules in CD8+ T cells. Partial virus clearance was dependent on CD8〈®+ cells. In vitro T cell re-stimulation assays demonstrated induction of a population of ®2M-dependent, MHC class Ib-restricted CD8+ T cells with specificity for viral antigen(s) and a yet to be defined nonclassical MHC molecule(s). MHC class Ib-restricted CD8+ T cell responses were also observed after infection of Kb−/−Db−/− mice, despite the low number of CD8+ T cells in these animals. Long term infection studies demonstrated chronic infection and gradual depletion of CD8+ T cells in Kb−/−Db−/−CIITA−/− mice, demonstrating that class Ia molecules are required for viral clearance. These findings demonstrate that class Ib-restricted CD8+ T cells have the potential to participate in the host immune response to LCMV.

Antigen-specific CD8+ T cell feedback activates NLRP3 inflammasome in antigen-presenting cells through perforin

“…The increased IL-1β in β2M-deficient spleen ( Fig. 7d ) is probably due to increased viral titre that has been reported 45 46 . We also used the LM bacteria or LCMV virus to infect wild-type or Perforin -deficient mice.…”

Nonclassical MHC Ib-restricted CD8+ T Cells Recognize Mycobacterium tuberculosis-Derived Protein Antigens and Contribute to Protection Against Infection

“…In fact, we found a substantial fraction of these Mtb-specific unconventional CD8 + T cells were restricted by Qa-2, which is known to present a more diverse array of peptides than other MHC Ib molecules [ 53 ]. Qa-2-restricted T cell responses have been implicated in anti-tumor immunity [ 48 ] and antiviral immunity [ 37 ] [ 54 ]. However, this is the first study to describe a role for Qa-2 in host defense against bacterial infection.…”

The role of MHC class Ib-restricted T cells during infection

“…While the exact restriction of this population is currently unknown, it is dependent on β2m and CD1d is dispensable (Braaten et al 2006). In addition, MHC class Ib-restricted T cells respond following lymphocytic choriomeningitis virus (LCMV) infection in both K b D b−/− and K b D b CIITA −/− mice, which also lack MHC class II molecules, however they were inadequate to fully clear the virus (Chen et al 2011). Non-classical T cells are also present in a wide range of species.…”