Review
The TNF family in T cell differentiation and function – Unanswered questions and future directions

https://doi.org/10.1016/j.smim.2014.02.005Get rights and content

Highlights

  • TNF/TNFR superfamily proteins are major regulators of T cells.

  • OX40, CD27, GITR, DR3, CD30, 4-1BB, TACI, and TNFR2 promote clonal expansion and T cell memory.

  • Fas, TNFR1, and TRAILR promote apoptotic death and limit T cell activity.

  • There are many unknowns regarding their function, expression, and integration in T cell responses.

  • Knowledge of how they control T cells will help fulfill their promise as targets for clinical therapy.

Abstract

Proteins in the TNF/TNFR superfamily are recognized as major regulators of the activity of conventional CD4 and CD8 T cells, and also of regulatory T cells (Treg). Stimulatory molecules such as OX40, CD27, GITR, DR3, CD30, 4-1BB, TACI, and TNFR2 can promote division and survival in T cells, enhance effector activity including cytokine production, and drive the generation of T cell memory. They also display the capacity to block the development of inducible Treg cells or inhibit suppressive activity in Treg cells. Additionally, molecules such as Fas, TNFR1, and TRAILR promote apoptotic death in T cells and generally limit T cell activity. Although our knowledge of these proteins is quite good at this point in time, there are still many unknowns regarding their function, their expression patterns, and the involvement of these different molecules at various stages of the T cell response that occurs in autoimmunity, cancer, infectious disease, and during vaccination. Importantly, it is still unresolved how similar or dissimilar each of these receptors are to one another, the extent to which cooperation occurs between family members, and whether alternate TNF–TNFR interactions induce qualitatively different cellular responses. All of the molecules are attractive targets for immunotherapy of human disease, but it is not yet clear how to differentiate between them and make an informed decision as to whether any one protein may be the preferred focus of clinical development for a given specific disease indication. This review will highlight unanswered questions related to these molecules and the biology of T cells, and describe possible future directions for research in this area. Expanding our knowledge of how the TNF/TNFR family control T cells will undoubtedly help fulfill the promise of these molecules for providing efficacious clinical therapy of immune system disease.

Introduction

A protective or pathogenic immune response often relies on the ability of either CD4 or CD8 T cells, or both subsets, to accumulate in high numbers as effector cells and to gain strong functional activity (often displayed as Th1/Th2/Th17 or CTL phenotypes). This equally applies to responses against foreign antigens expressed by infectious agents and to responses against self-antigens in autoimmune disease or in cancer. The initial T cell response occurs over 3–7 days in a primary response and more rapidly in recall responses. In some cases, CD4 or CD8 T cells may also differentiate into regulatory cells (inducible or iTreg) that afford tolerance and protect against damaging self-reactivity, as well as inadvertently hindering anti-tumor and anti-pathogen immunity. Additionally, CD4 T cells differentiate into follicular helpers (Tfh) to promote B cell immunity and antibody production within a slightly longer period, generally 5–15 days. Collectively, this is ample time for T cells to have multiple interactions with a number of different antigen-presenting cells (APC), including B cells, as well as potential contact with other T cells, other lymphoid cells, and non-lymphoid cells such as stromal cells, epithelial cells and endothelial cells. Each individual encounter with a T cell will engage many cell surface protein receptor–ligand pairs that direct, modulate, and control the activity of that T cell, and as such these receptor–ligand interactions can be viewed as the critical checkpoints for development and persistence of T cell immunity.

The receptors on T cells can include classical costimulatory molecules like CD28, and cytokine receptors such as IL-2R, that can promote clonal expansion; other cytokine receptors like IL-4R, IL-6R, IL-12R, TGF-βR, and IL-23R that promote alternate T cell subsets to develop including iTreg cells; and adhesion molecules and chemokine receptors that direct migration and trafficking between lymphoid tissue and peripheral tissue. Importantly, accumulating evidence over the past 10–15 years has highlighted the contributions of many molecules in the TNF and TNFR superfamilies to different aspects of the response of T cells [1], [2], [3], [4], [5].

The signals from engagement of TNF family receptors and ligands have often been generalized as controlling survival versus death in T cells, and this certainly encompasses a large part of their activity. TNFR family interactions can dramatically modulate the frequency of antigen-reactive T cells that accumulate at various stages of the immune response, either because the TNFR family members signal to induce anti-apoptotic proteins or proteins promoting cell division, or because they signal to induce pro-apoptotic molecules. However, other regulatory events such as enhancing cytokine secretion or chemokine receptor expression may be just as important.

The stimulatory or survival-inducing TNFR family members that have been characterized as expressed by T cells, and shown to promote T cell clonal expansion or pro-inflammatory activities in T cells, are OX40 (CD134), 4-1BB (CD137), CD27, GITR (CD357), CD30, HVEM (CD270), DR3, TACI (CD267), and TNFR2 (CD120b). In contrast, inhibitory or death-inducing molecules in the TNFR superfamily that can be found on T cells are Fas (CD95), TRAILR1 and TRAILR2 (DR4/CD261, DR5/CD262), and TNFR1 (CD120a), and these can restrict T cell accumulation. Furthermore, many TNF family ligands can also be expressed on T cells, like CD40L (CD154), LIGHT (CD258), LTαβ, OX40L (CD252), 4-1BBL, and CD70 (CD27L). The most often cited concept regarding why these latter molecules are on T cells is that they primarily act as ligands to induce functional activity via their cognate receptors expressed on cell-types that T cells encounter, including professional APC, neighboring T cells, and other lymphoid or non-lymphoid cells. This is exemplified by CD40L and LTαβ that can promote division and survival in APC through CD40 and LTβR, respectively. Molecules like CD40L and LTαβ additionally can function in feedback regulation, whereby signals through their receptors on APC or other cell-types leads to the upregulation of more stimulatory TNF family ligands such as OX40L, 4-1BBL, and CD70, hence indirectly allowing amplification of the T cell response.

Other TNF family ligands are produced as soluble molecules by T cells and essentially act like inflammatory cytokines. Their activity again can be manifest through promoting responses in non-T cells, or they can simply function in paracrine or autocrine fashion on T cells. For example, LIGHT produced by T cells in membrane form or as a soluble molecule can promote survival signals in other T cells through binding its receptor, HVEM, or it can promote cytokine production by binding HVEM on cells such as eosinophils or epithelial cells. Most notably TNF, FasL, and TRAIL are also produced as membrane or soluble molecules, and function as cytotoxic effector proteins when made by CD8 T cells and Th1 cells. These molecules are particularly important for controlling viral replication as well as other regulatory events in immune responses.

Given the quite extensive literature at this point in time, the question is then do we know all we need to know about TNF/TNFR molecules and their control of, or participation in, T cell responses? The answer is an emphatic no. This review will not attempt to catalog what we do understand about individual TNF/TNFR members, as this has been done before [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], but rather will try to highlight areas where our knowledge is poor or lacking, and where we might benefit from more basic and applied experimentation. There has been fantastic success with the TNF blockers in autoimmune disease, and biologics that neutralize BAFF and RANKL (also in the TNF family), or kill CD30-positive tumor cells, are now additionally on the market [4], but none of these are principally thought to be directed against T cell activity. Biologics to neutralize several TNF family molecules (LIGHT, OX40L, CD40) are in clinical trials for T cell-mediated inflammatory disease and agonists to several TNFR members (4-1BB, OX40, CD27, CD40, GITR) are being tested to augment T cell immunity in cancer, with others family members also being considered as possible therapeutic targets [4]. However, arguably, we do not yet know how best to target the TNF/TNFR superfamily to modulate T cell-driven disease, and we do not understand which TNF superfamily interaction or individual molecule would be the preferable target for any particular disease indication. These are primary goals for the research community, but before we can easily address them, fundamental questions in T cell biology still need to be answered.

Section snippets

Control of T cell clonal expansion and accumulation

The initial response of a naïve T cell is often separated into three phases, namely expansion, contraction, and memory generation. As mentioned above, signals through a large number of TNFR family molecules (OX40, 4-1BB, CD27, GITR, CD30, HVEM, DR3, TACI, TNFR2) have been shown to promote clonal expansion and the accumulation of high numbers of antigen-specific effector-type T cells in mouse models ranging from basic immunization schemes with nominal antigen to responses against viruses to

Development of subpopulations of effector and memory T cells

Another aspect of TNF family biology that relates to T cell responses is whether different TNF/TNFR interactions selectively expand, or drive the development of, alternate subsets of T cells. Here, we can firstly think of this simply in terms of CD4 versus CD8 T cells. For example, some literature suggests 4-1BB and CD27 are more important for driving accumulation of CD8 T cells compared to CD4 T cells, and other literature that OX40 is more important for CD4 T cell responses. Understanding to

Clonal contraction, and persistence and reactivation of memory T cells

As well as TNFR molecules driving the earlier phases of T cell responses to promote division and survival, lineage commitment, memory generation, and homing, these molecules also may influence T cell responses at a later time after the peak of the effector response. Generally, T cells undergo contraction in numbers at the population level, during which many die and only a proportion survive becoming memory cells. Whether TNFR family members play a strong and universal role in controlling the

Modulation of regulatory T cell activity

There is little doubt that regulatory T cells (Treg) are a major part of T cell biology and their accumulation and/or activity will impact the accumulation and activity of effector and memory T cells. Two primary types of CD4+ Treg cells have been described, thymic-derived or natural Treg (nTreg), and inducible or adaptive Treg (iTreg) that differentiate from naïve and perhaps memory T cells [35], and CD8 T cells can also exert Treg activity.

A number of studies of OX40, 4-1BB, TNFR2, and GITR

Signal transduction in T cells

Lastly, is the more basic issue of how TNF family receptors signal in T cells. In many respects, we will not fully understand how TNFR molecules control T cell activity until we know how they recruit intracellular adapters and kinases and positively or negatively control gene transcription. Our knowledge of how the death receptors (Fas, TRAILR, TNFR1) form signaling complexes and exert their activity through FADD/TRADD-driven caspase pathways is very good, including how TNFR1 can switch to

Conclusions

Research into how the TNF/TNFR superfamily controls and modulates T cell responses has progressed well over the past 10 years. Although fundamental knowledge of the immune system is good at any level, our primary goal should be to learn how to manipulate human immune system diseases. Indeed, studies have progressed to the stage that biologics that block or stimulate many of the TNF family receptors or ligands are being widely discussed as candidates for targeting T cell-driven processes, and

Disclosure

M.C. has licensed patents on several TNFSF/TNFRSF molecules.

Acknowledgements

M.C. is supported by NIH grants CA91837, AI49453, AI089624, AI100905, and AI070535. This is publication #1683 from the La Jolla Institute for Allergy and Immunology.

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