Association ofCTLA4 polymorphism with regulatory T cell frequency

Abstract

A common single nucleotide polymorphism in CTLA4 has been linked with susceptibility and outcome in autoimmune and infectious diseases, respectively. Here, we show that this polymorphism is associated with the frequency of CD4 + CD25 + regulatory T cells in healthy human volunteers. We further show that, on a per cell basis, such regulatory T cells appear to be functionally indistinguishable across CTLA4 genotypes. These data implicate CTLA4 in regulatory T cell development, and provide a mechanism to account for the link between polymorphisms at this locus and the biological outcome of adaptive immune responses to self and to pathogens. IntroductionInhibition is as important as activation in regulating the vigor of immune responses. Among a variety of inhibitory pathways, attention has focused on CTLA-4, an immunoglobulin superfamily member that plays a key role in restraining T cell responses [1, 2]. Common single nucleotide polymorphisms (SNP) in CTLA4 have been associated with disease susceptibility and outcome in autoimmune diseases and viral hepatitis, respectively [3][4][5]. CTLA4 alleles associated with increased susceptibility to autoimmune disease are also associated with increased clearance of hepatitis B virus infection; similarly alleles associated with protection from autoimmune disease are also associated with reduced clearance of hepatitis B virus infection [4, 5]. Such associations have biological plausibility: decreasing the vigor of T cell responses would be expected to decrease susceptibility to tissue-destructive autoimmune processes as well as to decrease the likelihood of clearing viral infection.The field of immune regulation has been revolutionized by the recent identification of a specialized population of suppressor CD4 + T cells [6, 7]. Characterized phenotypically by constitutive expression of IL-2Ra (CD25), these cells were first identified by their role in maintaining self tolerance. Subsequently, CD4 + CD25 + T cells (Treg) have also been shown to play a central role in restraining the vigor of immune responses to pathogens [8][9][10][11][12][13][14][15]. While CTLA-4 was classically thought to restrain T cell responses by acting in cis on activated T cells [1], it has become clear that CTLA-4 can also act in trans [16,17]. Notably, Treg constitutively express CTLA-4, and Treg-mediated inhibition of T cell responses is due to CTLA-4 in a variety of experimental systems [6, 7,[18][19][20][21][22][23]. In addition to being part of the effector armamentarium of Treg, however, data from mouse models are compatible with a role for CTLA-4 in Treg development [23,24]. We thus hypothesized an influence of CTLA4 polymorphisms on Treg development. (Fig. 1a).No such correlation of genotype and Treg frequency was found for another well-characterized polymorphism (+49; exon 1) in CTLA4 (Fig. 1b). Of interest, this latter polymorphism is in linkage disequilibrium with the CT60 SNP. All volunteers homozygous for the A allele at CT60 were also homozygous for the A allele at +49, but the reverse ...

Allelic variant inCTLA4alters T cell phosphorylation patterns

“…However, we do not propose that the level of CTLA4 expression, which may be indirectly related to the CT60 allele, is associated with the altered responsiveness to TCR stimulation of CD4 ϩ CD45RA high and CD4 ϩ CD45RA low T cells because we have not observed any significant differences in total CTLA-4 expression in these two populations among a subset of subjects in the three genotype classes (data not shown). This observation may not be surprising because it is the mRNA species encoding a soluble CTLA-4 isoform that has been associated with the CT60 allele (6,10). Its measurement at the protein level is, as yet, not possible because of the lack of suitable mAbs for this isoform.…”

“…One well validated region associated with susceptibility to autoimmune disease harbors the CTLA4 gene on chromosome 2q33. An associated allele in this susceptibility region is the G allele of the SNP CT60 (rs3087243; A/G) in the CTLA4 gene region, which has been associated with risk to type 1 diabetes, Graves disease, autoimmune hypothyroidism, systemic lupus erythematosus, and Addison's disease (6)(7)(8)(9)(10).…”

“…Moreover, the genotype-dependent difference in the expression of soluble CTLA4 transcripts appears to be T cell-specific (6,10). In the nonobese diabetic (NOD) mouse, the orthologous CTLA4 region also is associated with autoimmune diabetes, and, similar to humans, an allelic variant causes the increased expression of a major splice isoform.…”

Autoimmunity and Apoptosis - Therapeutic Implications

“…Lack of costimulatory molecules and those which amend TCR signaling might also have a key role in establishing autoimmunity. Autotolerance modulatory effect of T regs is contact-dependent and is mediated by TGF-and CTLA4 immunoreceptors that have a regulatory role on T-cell proliferation [45][46][47]. Thus, T-cells expressing variant alleles of the genes that are associated with autoimmune conditions (e.g.…”

“…In CTLA4, genetic alterations in a 3' untranslated region (3'UTR) as well as a single nucleotide polymorphism (SNP) which encodes the substitution of a threonine to alanine was found to associate with autoimmune thyroid diseases and several other disorders such as insulin-dependent diabetus mellitus (IDDM), systemic lupus erythematosus (SLE), Addison's disease, multiple sclerosis (MS) and rheumatoid arthritis (RA) [5,[48][49][50][51]. The 3'UTR variant is also known to be associated with a reduced number of circulating T regs , indicating a controlling effect of this allele on development and lineage commitment of T-cells [46]. PTPN22 encodes lymphoid tyrosine phosphatase (LYP) which modulates the activity of Lck and other kinases involved in early events of signaling cascade mediated through TCR [52].…”