TNF superfamily: costimulation and clinical applications

Abstract

The molecules concerned with costimulation belong either to the immunoglobulin (Ig) or tumor necrosis factor (TNF) superfamily. The tumor necrosis superfamily comprises molecules capable of providing both costimulation and cell death. In this review we briefly summarize certain TNF superfamily receptor-ligand pairs that are endowed with costimulatory properties and their importance in health and disease.

Figure 1. Schematic cartoon depicting members of TNF superfamily

Each member of the TNF superfamily is indicated by its scientific nomenclature. The description in the parentheses denotes their common name. Since the expression of a particular TNF receptors or its ligand is not exclusive to a particular cell type and sometimes present on the same cell, a generalized depiction illustrated.

Figure 2. Schematic representation of important members of TNF superfamily

Although some the members of the family are constitutively expressed (low levels), in most cases their expression is activation dependent. The expression of given receptor or ligand is not restricted to a particular cell and can sometimes present on both T lymphocyte as well as antigen presenting cell enabling a bidirectional signaling cascade.

Figure 3. CD27-CD70 pathway

Signaling via CD27-CD70 pathways provides positive immune regulation. When stimulated with appropriate agonist such as anti-CD27 or anti-CD70 or cell lines made to express these molecules relay signals through TRAF2/5 resulting in long-term survival of cells via induction of NIK and NF-κB. Signals also result lead to the expression of PI3 kinase, ERK1/2, PLCγ leading to robust cell division.

Figure 4. CD30-CD153 pathway

Expression of CD30 or CD153 is not exclusive and can be present on both T cells as well as APCs. Such variable expression pattern of CD130-CD153 results in diverse immune responses. Interaction of CD153 bearing T cell with CD30⁺ B cell enhances survival gene expression leading cell division and increased antibody production. On the other hand, CD30⁺ T cells interaction with CD153⁺ B cell results in reduced Antibody production.

Figure 5. CD134-CD134L pathway

CD134 is transiently expressed on T cells and is known to support late immune responses. Once expressed and when stimulated via TCR or agonistic anti-CD134 mAbs or cells made to express CD134L supports cell division and IL-2 production resulting in long-term survival of memory T cells.

Figure 6. CD137-CD137L pathway

With a few exceptions expression of CD137 is activation dependent. There is a variability in anti-CD137-mediated signaling. While in vitro anti-CD137 stimulation supports activation of both CD4+ and CD8+ T cells, in vivo effects mediated by anti-CD137 is complex. Administration of agonistic anti-CD137 mAbs supports robust CD8+ T cell expansion and constricts CD4+ T and B cell numbers and function. This latter in vivo effect of anti-CD137 is believed to result from over expression of IFN-γ, IL-10, TGF-β, granzymeB, perforin, and CTLA-4 and expansion of a novel immunoregulatory CD11c+CD8+ T cell subset. The increased IFN-g due to anti-mediated CD11c+CD8+ T cells upregulates indoleamine 2,3-dioxygenase (IDO) in competent cells which when interact with partnering CD4+ T cells causes their deletion. This can be reversed by neutralizing IDO activity by 1-mehtyltryptophan.

Figure 7. CD40-CD154 pathway

Expression of CD40 is widespread on a variety cells including CD4+ T cells. CD40 binds an activation induced CD154 molecule. Interaction of CD154+ CD4+ T cells with CD40-bearing cells results in the activation of partnering cells resulting in the expression of cell survival genes, cytokine induction, Ig isotype switching etc.

Figure 8. GITR-GITRL pathway

Expression of GITR is activation dependent with the exception of Foxp3+ Tregs which express this antigen in a constitutive manner. Signals through GITR are co-stimulatory in nature to CD4+ and Cd8+ T cells resulting cell division and cytokine induction. Importantly, GITR provides key signals to FoxP3+ Tregs to maintain immune tolerance and plays a critical role in the control of autoimmune diseases.

Figure 9. HVEM-LIGHT pathway

HVEM was originally identified as entry mediator of herpes virus. HVEM signaling is complex as it binds KIGHt as well as LTα3 and is further complicated as LIGHT besides binding HVEM also binds LTRβ. This complex receptor-ligand interactions as well as HSV-HVEM interplay culminate in the expression of of array of signaling molecules, type I IFNs etc.