Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses

Abstract

Members of the TNFR family are thought to deliver costimulatory signals to T cells and modulate their function and survival. In this study, we compare the role of two closely related TNFR family molecules, OX40 and 4-1BB, in generating effector CD8 T cells to Ag delivered by adenovirus. OX40 and 4-1BB were both induced on responding naive CD8 T cells, but 4-1BB exhibited faster and more sustained kinetics than OX40. OX40-deficient CD8 T cells initially expanded normally; however, their accumulation and survival at late times in the primary response was significantly impaired. In contrast, 4-1BB-deficient CD8 T cells displayed hyperresponsiveness, expanding more than wild-type cells. The 4-1BB-deficient CD8 T cells also showed enhanced maturation attributes, whereas OX40-deficient CD8 T cells had multiple defects in the expression of effector cell surface markers, the synthesis of cytokines, and in cytotoxic activity. These results suggest that, in contrast to current ideas, OX40 and 4-1BB can have a clear functional dichotomy in modulating effector CD8 T cell responses. OX40 can positively regulate effector function and late accumulation/survival, whereas 4-1BB can initially operate in a negative manner to limit primary CD8 responses.

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

“…Both 4-1BB and OX40 interact with common TRAF proteins, activate NFkB pathways and induce expression of anti-apoptotic Bcl-2 family molecules [42][43][44]. Such overlap might suggest some redundancy in function, with consequently less potential for synergy, although deficiencies in either 4-1BB or OX40 on CD8 1 T cells result in impaired T-cell responses [15], indicating that signalling through both is necessary for optimal function. However, there are differences between the in vivo expression patterns of the two molecules, with expression of OX40 on CD8 1 T cells occurring slightly later than that of 4-1BB, and being more transient [31], suggesting that their signalling might be important at different time points during the T-cell response.…”

“…However, there are differences between the in vivo expression patterns of the two molecules, with expression of OX40 on CD8 1 T cells occurring slightly later than that of 4-1BB, and being more transient [31], suggesting that their signalling might be important at different time points during the T-cell response. In addition, studies directly comparing the function of 4-1BB-and OX40-deficient CD8 1 T cells indicate distinct differences between the roles of the two molecules [15]. In particular, OX40 appears to be important in the acquisition of effector function, with activated OX40-deficient CD8 1 T cells demonstrating reduced expression of granzyme B, TNF and IFN-g. Dual co-stimulation with anti-OX40 and anti-4-1BB could therefore enhance effector function as well as T-cell survival.…”

“…However, recently apparently contradictory evidence has shown that anti-4-1BB mAb can also suppress humoral immunity, airway allergic responses and numerous autoimmune responses [15], thus perhaps triggering 4-1BB skews responses, even when fully established, away from Th2 and towards Th1 [16,17]. Such a dichotomy of functions has been suggested to make it ideal for tumour vaccines, particularly for combining with agents that are known to promote autoimmunity as a side-effect of tumour therapy [18].…”

Monosomy 1p36 uncovers a role for OX40 in survival of activated CD4+ T cells

“…While studies of OX40 deficient mice have helped to elucidate the role of OX40, heterozygous mice have not been specifically characterized. Many studies using murine models provide evidence that OX40 plays a more important role in generating a secondary response to viral and protein antigens by inducing anti-apoptotic proteins such as Bcl-xl and promoting survival of CD4 T cells upon ligation [12,11,36,24,13,15,37,22,23,38]. Through these signals, OX40 is thought to increase the number of effector cells that can then enter the memory cell pool [11,6,39].…”

Enhanced antitumor activity mediated by human 4‐1BB‐engineered T cells

“…3 Its expression on activated CD8 1 T cells is very fast and transient 3 though it might last for several days if the antigen persists. 10 4-1BB signaling induced in vitro by monoclonal antibodies or soluble 4-1BBL, in the presence of anti-T-cell receptor (TCR) antibody (Ab), has been shown to cause T-cell expansion, 11 increased cytokine secretion (mainly Th1 cytokines), 12,13 upregulation of antiapoptotic genes 14 and the prevention of activation-induced cell death 13,15 (reviewed also in Refs. 3,16) in both human and murine cells.…”