A Molecular Perspective of Ctla-4 Function

Abstract

Within the paradigm of the two-signal model of lymphocyte activation, the interest in costimulation has witnessed a remarkable emergence in the past few years with the discovery of a large array of molecules that can serve this role, including some with an inhibitory function. Interest has been further enhanced by the realization of these molecules' potential as targets to modulate clinical immune responses. Although the therapeutic translation of mechanistic knowledge in costimulatory molecules has been relatively straightforward, the capacity to target their inhibitory counterparts has remained limited. This limited capacity is particularly apparent in the case of the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a major negative regulator of T cell responses. Because there have been several previous comprehensive reviews on the function of this molecule, we focus here on the physiological implications of its structural features. Such an exercise may ultimately help us to design immunotherapeutic agents that target CTLA-4.

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

“…Increased levels of CTLA-4 are also characteristic of activated and memory T cells associated with downmodulation of CD28 4,29,30]. Almost all CTLA-4 1 T cells expressed CD28, but the level of CD28 expression in the CTLA-4 1 population in lupus T cells was significantly reduced compared with healthy controls (p 5 0.0001) (Fig.…”

“…Several mechanisms have been proposed to explain the molecular basis for CTLA-4 inhibition including a dampening of T-cell signalling responses and alterations in T-cell motility [4,5]. The location and interaction of CTLA-4 within membrane lipid microdomains also influences its inhibitory function.…”

Association of CTLA-4 gene promoter polymorphisms with systemic sclerosis in Iranian population

“…Moreover, CTLA-4 expression is increased by cAMP, suggesting a cAMPdependent regulation of CTLA-4 gene expression. 14 Significant increase of the CTLA-4 mutant alleles (À1722C, À1661G and À318T) and heterozygous genotypes (À1722 T/C, À1661 A/G and À318 C/T) in SSc patients rather than controls suggests that cytosine at position À1722, guanine at position À1661 and thymine at position À318 may affect the transcription level of the gene. In this regard, an association between CTLA-4 promoter genotypes at position À318 and levels of CTLA-4 molecule has been demonstrated.…”

“…mCTLA-4 upon binding to B7 molecules inhibits CD28/B7 interaction, resulting in downregulation of the immune response, 14 whereas increase in sCTLA-4 levels may block B7-mCTLA-4 interactions and thereby enhances T-cell activation and autoreactivity. In this regard, Sato et al 27 reported that increased levels of sCTLA-4 may be related to the abnormal immune response in SSc patients.…”

“…It is known, however, that CTLA-4 reduces the positive costimulatory signal delivered by CD28 through competition for ligand binding and interfering with downstream signaling molecules. Other mechanisms by which this molecule can negatively regulate T-cell functions include interfering with signals delivered by T-cell receptors (TCR), blocking IL-2 production, promotion of T-cell apoptosis, 14 inhibition of dendritic cell function by inducing tryptophan catabolism 16 and induction of immune suppressive cytokine TGF-b. 17 Moreover, CTLA-4 can regulate T-cell polarization to Thelper (Th) 1 or Th2 by controlling the overall strength of T-cell activation signal.…”