The significance of OX40 and OX40L to T-cell biology and immune disease

Abstract

OX40 (CD134) and its binding partner, OX40L (CD252), are members of the tumor necrosis factor receptor/tumor necrosis factor superfamily and are expressed on activated CD4(+) and CD8(+) T cells as well as on a number of other lymphoid and non-lymphoid cells. Costimulatory signals from OX40 to a conventional T cell promote division and survival, augmenting the clonal expansion of effector and memory populations as they are being generated to antigen. OX40 additionally suppresses the differentiation and activity of T-regulatory cells, further amplifying this process. OX40 and OX40L also regulate cytokine production from T cells, antigen-presenting cells, natural killer cells, and natural killer T cells, and modulate cytokine receptor signaling. In line with these important modulatory functions, OX40-OX40L interactions have been found to play a central role in the development of multiple inflammatory and autoimmune diseases, making them attractive candidates for intervention in the clinic. Conversely, stimulating OX40 has shown it to be a candidate for therapeutic immunization strategies for cancer and infectious disease. This review provides a broad overview of the biology of OX40 including the intracellular signals from OX40 that impact many aspects of immune function and have promoted OX40 as one of the most prominent costimulatory molecules known to control T cells.

Figure 1. OX40 signals determine the size of effector and memory T cell pools

Three models for effector and memory T cell generation are depicted. A) Upon activation, naïve CD4 T cells develop into either central memory cells (Tcm) or effector memory cells (Tem). The Tcm and Tem fate decision occurs early during priming, perhaps determined by antigen access and/or dose, before OX40 is ligated on recently activated naive T cells. OX40 signals promote clonal expansion and survival of Tem precursors that differentiate in a step-wise manner into true primary effector cells and then into resting Tem after antigen is cleared. Tcm precursors expand and enter into the central memory pool in an OX40 independent fashion. OX40 is critical to CD4 T cell memory because in general Tem predominate. B) Following activation of naïve CD8 T cells, they expand and develop into effector cells that may contain both Tcm and Tem precursors. In this context, OX40 signals promote clonal expansion and support survival of most effector CD8 T cells that enter into the memory pool regardless of their lineage potential, hence OX40 is critical to CD8 T cell memory generation. This situation might apply to responses against tumors, auto or allo-antigen, or select infectious agents. C) Activation of naïve CD8 T cells under other inflammatory conditions results in the daughter cells developing into SLEC (short-lived effector cells) and MPEC (memory precursor effector cells). During priming, OX40 promotes expansion and survival of MPEC and further inhibits conversion of MPEC into SLEC. At later times, most SLEC die, but multipotent MPEC survive and give rise to transitional Tem that progressively differentiate into long-lived Tcm. Furthermore, OX40 signals to MPEC provided during the primary effector phase impart signals to maintain the later self-renewing capacity of Tcm in the absence of antigen. This situation might apply to responses against select infectious agents, and again OX40 becomes critical for memory generation because of the control of MPEC.

Figure 2. The cytoplasmic tail of OX40 connects to intracellular signaling pathways

The diagram depicts the extracellular, transmembrane, and intracellular regions of mouse (top) and human (bottom) OX40. The cytoplasmic region contains residues crucial for costimulatory signaling. Arguably most important is the QEE motif, characteristic of many TNFR family molecules, that mediates binding to several TNFR-associated factors (TRAF) including TRAF2, TRAF3, and TRAF5. These are adaptors allowing OX40 to link to intracellular kinases. Mouse OX40 also contains a potential PI3K binding motif (PXXP) that could directly allow connection to the kinase, PKB (Akt). Furthermore, several lysine (K) residues (shown by arrows) are present which might allow OX40 to be ubiquitinated in lipid rafts. The function of the latter action is presently unknown, but might be important for downstream kinase activity.

Figure 3. OX40 activates PI3k/PKB, NF-κB1, and NFAT pathways to allow both antigen-dependent and antigen-independent signaling

OX40L binding to OX40 results in recruitment of TRAF2 and the formation of a signaling complex containing IKKα and IKKβ, as well as PI3k and PKB (Akt). This complex, upon translocation into lipid rafts, is sufficient to activate NF-κB1 in an antigen independent manner, via phosphorylation and degradation of IκBα, leading to entry of p50 and RelA into the nucleus. In contrast, OX40 ligation does not effectively lead to phosphorylation of PKB, but OX40 co-operates with TCR signals brought about by antigen recognition, to augment PKB activation, possibly reflective of a requirement to recruit and activate PDK1. OX40 also synergizes with TCR signals to augment intracellular Ca²⁺, through an unknown mechanism, that leads to enhanced nuclear import of NFAT. The downstream targets of these signaling pathways include upregulating genes that control T cell division and survival, and promoting transcription of cytokine genes, as well as expression of cytokine receptors. Suppressive events brought about by OX40 signaling include downregulation of CTLA-4 and Foxp3.