Modulation of NKT Cell Development by B7-CD28 Interaction: An Expanding Horizon for Costimulation

Abstract

It has been demonstrated that the development of NKT cells requires CD1d. The contribution of costimulatory molecules in this process has not been studied. Here we show that in mice with targeted mutations of B7-1/2 and CD28, the TCRβ+α-Galcer/CD1d + (iVα14 NKT) subset is significantly reduced in the thymus, spleen and liver. This is mainly due to decreased cell proliferation; although increased cell death in the thymi of CD28-deficient mice was also observed. Moreover, in the B7-1/2- and CD28-deficient mice, we found a decreased percentage of the CD4−NK1.1+ subset and a correspondingly increased portion of the CD4+NK1.1− subset. In addition, the mice with a targeted mutation of either B7 or CD28 had a reduced susceptibility to Con A induced hepatitis, which is known to be mediated by NKT cells. Our results demonstrate that the development, maturation and function of NKT cell are modulated by the costimulatory pathway and thus expand the horizon of costimulation into NKT, which is widely viewed as a bridge between innate and adaptive immunity. As such, costimulation may modulate all major branches of cell-mediated immunity, including T cells, NK cells and NKT cells.

Cutting Edge: CD28 Engagement Releases Antigen-Activated Invariant NKT Cells from the Inhibitory Effects of PD-1

“…The development of innate-like T cells, including iNKT cells, requires specific signals mediated by Slamf receptor/SAP adaptor, as well as CD28 (14,15,18,19 phenotype similar to that seen in WT thymic iNKT cells (Fig. 2d).…”

“…The reduced serum cytokine levels in ␣GalCer-treated, CD28-deficient mice might be the result of impaired development of iNKT cells (14,15). Therefore, we determined the percentages and absolute numbers of iNKT cells in the thymus and spleen of WT and CD28 Ϫ/Ϫ or CD80/CD86 Ϫ/Ϫ mice.…”

“…Evidence also shows that the cytokine production competency of iNKT cells is established during thymic development (13). CD28 signaling appears to contribute to positive selection/maturation of thymic iNKT cells and other innatelike T cells (14,15), but it remains unclear whether the lack of CD28 signaling during thymic development fosters the generation of cytokine production-incompetent iNKT cells.…”

Immunological in vivo effects of B7-H1 deficiency

“…They also participate in the immune regulatory network-the suppressive function of NKT cells has been described in the recent past [56], as has their interaction with Treg [55]. Interestingly, the B7-CD28 co-stimulatory pathway can modulate development of NKT cells [57,58] and PD-1/PD-L1 interaction is essential for the induction and maintenance of iNKT cell anergy. PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells in the melanoma model [59].…”

Targeting NKT cells and PD-L1 pathway results in augmented anti-tumor responses in a melanoma model

“…In contrast, other studies have shown no role for these pathways in the initial cytokine production by iNKT cells but costimulation was important for the expansion and subsequent systemic cytokine production by NKT cells [9, 10]. Recent studies indicate that the B7:CD28 pathway might be important in the development of iNKT cells [11, 12]. Newly discovered costimulatory molecules also have been implicated in the function of iNKT cells.…”