A role for CD1d-restricted NKT cells in injury-associated T cell suppression

Abstract

Natural killer T (NKT) cells are known to modulate T cell responses during autoimmunity, tolerance, and antitumor immunity; however, their potential role in regulating the immune response to injury has not been reported. Using a murine model of burn injury, we investigated whether CD1d-restricted NKT cells played a role in the T cell suppression that occurs early after injury. A functional role for CD1d stimulation of NKT cells in the injury-related immune suppression was demonstrated by experiments in which the suppression of antigen (Ag)-specific delayed-type hypersensitivity and in vitro T cell-proliferative responses were prevented if mice were given anti-CD1d monoclonal antibody (mAb) systemically just before injury. The CD1d-NKT cell-dependent suppression of the T cell response after injury occurred in the absence of quantitative changes in NKT cells themselves or CD1d(+) Ag-presenting cells. We observed that elevated production of the immunosuppressive cytokine interleukin (IL)-4 correlated with burn-induced immune dysfunction, and we found that NKT cells but not conventional T cells were the source of IL-4 early after injury. Lastly, we observed that the injury-induced production of NKT cell-derived IL-4 could be blocked by systemic treatment of burn-injured mice with anti-CD1d mAb. Together, our results reveal a novel mechanism involving CD1d stimulation of NKT cells in the onset of T cell suppression that occurs subsequent to injury.

Injury-Induced Suppression of Effector T Cell Immunity Requires CD1d-Positive APCs and CD1d-Restricted NKT Cells

“…Moreover, the DTH responses of burn-injured CD1d ko mice were ϳ3-fold greater in magnitude compared with burn-injured WT mice. The observation that CD1d-deficient sham-treated mice had lower DTH responses than their WT counterparts is in line with studies by others identifying a role for NKT cells in amplifying T cell immunity and with our previous reports that showed lower OVA-specific DTH responses in WT mice treated with anti-CD1d mAb systemically (8).…”

“…We recently identified a role for CD1d stimulation of NKT cells in injury-induced suppression of T cell immunity (8). In this study, we expand upon those initial findings and identify a critical requirement for both CD1d expression and NKT cells themselves in the immune dysfunction that occurs early after burn injury.…”

“…In contrast, IL-4 production was not elevated in response to injury in CD1d ko mice, nor was IFN-␥ production impaired. Although we did not examine NKT cell-derived IL-4/IFN-␥ per se in this experiment, we previously reported that at 24 h after burn injury, the only cells in the spleen that produce IL-4 are CD1d-restricted NKT cells (8). The effects of cytokines from other cell types within the cultures (i.e., T cells, NK cells, APCs, etc.)…”

“…We previously reported that during the first 24 h after burn injury, NKT cells fail to produce IFN-␥ and acquire a predominantly IL-4-producing phenotype (8). In this study, we examined the production of IFN-␥ and IL-4 in splenic lymphocyte cultures from sham-vs burn-injured WT vs CD1d ko mice collected at 24 h after injury and given polyclonal stimulus in vitro.…”

“…Investigations over the past two decades have provided new insight into the roles of macrophages, dendritic cells, and T lymphocytes in regulating immunity during injury and sepsis (11)(12)(13). With the exception of a few isolated reports (8,14), modulation of the immune response to injury by less numerous, nonconventional lymphocyte populations, such as ␥-␦ T cells, regulatory T cell subsets, and CD1d-restricted NKT cells in particular, has remained largely unexplored.…”