Studies of T-cell activation in chronic inflammation

Abstract

The strong association between specific alleles encoded within the MHC class II region and the development of rheumatoid arthritis (RA) has provided the best evidence to date that CD4+ T cells play a role in the pathogenesis of this chronic inflammatory disease. However, the unusual phenotype of synovial T cells, including their profound proliferative hyporesponsiveness to TCR ligation, has challenged the notion that T-cell effector responses are driven by cognate cartilage antigens in inflamed synovial joints. The hierarchy of T-cell dysfunction from peripheral blood to inflamed joint suggests that these defects are acquired through prolonged exposure to proinflammatory cytokines such as tumour necrosis factor (TNF)-alpha. Indeed, there are now compelling data to suggest that chronic cytokine activation may contribute substantially to the phenotype and effector function of synovial T cells. Studies reveal that chronic exposure of T cells to TNF uncouples TCR signal transduction pathways by impairing the assembly and stability of the TCR/CD3 complex at the cell surface. Despite this membrane-proximal effect, TNF selectively uncouples downstream signalling pathways, as is shown by the dramatic suppression of calcium signalling responses, while Ras/ERK activation is spared. On the basis of these data, it is proposed that T-cell survival and effector responses are driven by antigen-independent, cytokine-dependent mechanisms, and that therapeutic strategies that seek to restore T-cell homeostasis rather than further depress T-cell function should be explored in the future.

Figure 1

Acquisition of transcriptional competence during differentiation of T helper cells. Th cells become productive effectors of immunoinflammatory responses following a complex series of molecular events dependent upon membrane-proximal TCRs and cytokine receptor signals. Chromatin remodelling is an essential step in the process leading to a switch from the 'closed' to 'open' DNA conformation. This in turn permits accessibility of Th-subset-specific transcription factors and accessory factors to the promoter elements of the Th2 gene cluster, as illustrated here. Ultimately, NFAT is recruited to the transcriptosome, after which cytokine gene transcription proceeds. c-Maf, transcription factor specific for Th2 cells; ERM, transcription factor specific for Th1 cells; GATA-3, transcription factor specific for Th2 cells; NFAT, nuclear factor of activated T cells; STAT, signal transducer and activator of transcription; T-bet, transcription factor specific for Th1 cells; TCR, T-cell receptor; Th, T helper (cell).

Figure 2

A model for the role of CD4⁺ T cells in the pathogenesis of chronic inflammation. Antigen drive predominates during the early phase of inflammatory responses ('antigen mode'). In a nonsusceptible host, the immune response resolves through mechanisms such as activation-induced cell death and/or the production of immunoregulatory cytokines. In the susceptible host, additional T cells are recruited to sites of inflammation through bystander activation, or by stimulation with self antigens released from inflamed tissues. As the inflammatory process progresses, chronic cytokine production induces profound nondeletional T-cell hyporesponsiveness. Hyporesponsive T cells function as effector cells and sustain the chronic inflammatory process through predominantly antigen independent mechanisms ('inflammation mode'). It is proposed that by reversing T-cell hyporesponsiveness, antigen-dependent responses that serve to regulate the inflammatory process (e.g. through expression of immunoregulatory cytokines) are restored.

Figure 3

Model for studying the effects of TNF on T-cell differentiation and maturation. T cells are stimulated with cognate antigen in the presence of irradiated antigen-presenting cells for periods of up to 14 days in the presence or absence of recombinant TNF. Cytokines are added to cultures every 2 or 3 days. At the end of the culture period, T cells are washed extensively and then rechallenged with specific antigen or anti-CD3 mAb in the absence of TNF. APC, antigen-presenting cell; T, T cell; TNF, tumour necrosis factor-α.

Figure 4

The immunomodulatory effects of TNF during the evolution of the immune response. After TCR ligation, TNF is costimulatory and required for antigen priming. As the immune response proceeds over time, TNF is required to suppress subsequent clonal expansion (TNF^+/+; unbroken line). In TNF-deficient animals (TNF^-/-; dotted line), immune responses are delayed, but, once established, they fail to resolve, leading to persistent antigen reactivity. TNF, tumour necrosis factor-α.

Figure 5

Assembly and degradation of the TCR/CD3 complex. TCRζ and TRIM are required for assembly and stability of the TCR/CD3 complex at the cell surface (see text for further details). ER, endoplasmic reticulum; TCR, T-cell receptor; TRIM, T-cell-receptor-interacting molecule.

Figure 6

The calcium/calcineurin/NFAT signalling pathway in T cells. After TCR ligation and PLCγ1 activation, newly synthesized IP3 binds to tetrameric IP3 receptor complexes inducing the release of intracellular calcium stores from the sarco-endoplasmic reticulum. Store depletion leads directly to the opening of I_CRAC or store-operated channels (SOC) in the plasma membrane through mechanisms that are unclear. This leads ultimately to activation of the serine phosphatase calcineurin, dephosphorylation of NFAT, and translocation of this transcription factor to the nucleus. For many genes, NFAT binds cooperatively to AP-1 complexes for optimal gene transcription. AP, activator protein; CsA, cyclosporin A; iCa²⁺, intracellular calcium; I_CRAC, calcium-release-activated calcium current; IP, inositol phosphate; P, phosphate group; PLCγ, phospholipase Cγ; TCR, T-cell receptor.

Figure 7

TCR signal transduction pathways. Engagement and stabilisation of TCR/CD3 complexes leads to a membrane-proximal cascade of tyrosine phosphorylation events that ultimately lead to the activation of kinases and transcription factors directly involved in gene transcription. Ligation of TCR and costimulatory receptors leads to activation of multiple pathways, including ERK, JNK, NF-κB, and NFAT (left panel). Impaired assembly and stability of the TCR/CD3 complex would be expected to attenuate all downstream pathways (middle panel). However, chronic TNF stimulation leads to selective uncoupling of TCR signalling, such that TCR-induced calcium/NFAT responses are impaired, while Ras/ERK activation is spared (right panel). The effects of proinflammatory cytokines on the activation of these specific pathways are not included here. ERK, extracellular signal-regulated kinase; Jnk, c-Jun N-terminal kinase; NF, nuclear factor; NFAT, nuclear factor of activated T cells; TCR, T-cell receptor.