Recent years have seen an explosion of genome-wide association studies (GWAS) designed to identify, in an unbiased manner, genetic loci associated with complex polygenic traits and diseases, including several autoimmune diseases (1). However, defining the functional consequences of disease-associated SNPs has been extremely challenging for several reasons. First, the majority of SNPs linked to polygenic autoimmune diseases individually confer a modest relative risk of developing disease (with odds ratios less than 1.5), suggesting that a complex genetic environment is required to manifest disease. Second, it is possible that some disease-associated SNPs are not causative, but instead act as genetic markers for rare disease-causing SNPs located nearby. Last, most disease-associated SNPs are noncoding, so it is likely that subtle and cell type–specific changes in transcript expression or splicing confer susceptibility to disease. Defining such subtle changes in gene expression has been difficult, and direct study of noncoding SNPs in model organisms or cell lines in order to define their effects on disease pathogenesis has not been possible.

TCPTP is a ubiquitous non-receptor protein tyrosine phosphatase, with highest expression detectable in hematopoietic tissues and predominantly nuclear localization (2). Although TCPTP-deficient mice are born at Mendelian ratios, they become ill and die by three to five weeks of age (5). This early-onset disease is characterized by inflammatory infiltrates in multiple organs (6). Notably, these mice exhibit a dramatic increase in expression of proinflammatory cytokine transcripts in various tissues, including those encoding TNF-α, IFN-γ, and IL-12 (6). However, the site and stimulus for this increased cytokine production are unclear, as analysis of bone marrow chimeric mice indicates that TCPTP plays a critical regulatory role in both hematopoietic and non-hematopoietic cells (2).

Modeling the functional consequences of noncoding disease-associated SNPs has been challenging. Direct study of primary cells from patients or healthy controls harboring disease-associated SNPs offers a powerful approach. Recently, Buckner and colleagues reported a modest (25%) reduction in expression of PTPN2 transcripts in primary human T cells harboring an intronic PTPN2 SNP associated with type 1 diabetes (10). They went on to probe the IL-2 signaling pathway and reported subtly impaired STAT5 phosphorylation in CD25⁺ regulatory T cells and CD45RO⁺ memory T cells bearing the disease-associated PTPN2 SNP. By contrast, it has been previously shown that TCPTP-deficient mouse T cells exhibit enhanced JAK/STAT phosphorylation upon IL-2 stimulation (7, 8). Reconciling these disparate results will be important for our understanding of how the PTPN2 locus contributes to disease pathogenesis. Importantly, TCPTP is ubiquitously expressed, and disease-associated SNPs may affect expression or splicing in many other tissues as well. It is possible, for example, that PTPN2 polymorphisms contribute to type 1 diabetes not only through immunologic pathways, but also by direct regulation of insulin receptor signaling (2).

The studies described in the previous section suggest how subtle alterations in TCPTP expression in T cells and other tissues could account for the disease association of noncoding SNPs in PTPN2. However, the precise function of TCPTP in T cells, key effectors in the pathogenesis of many autoimmune diseases, has not been well studied, in part because of the inflammation and mortality associated with global TCPTP deficiency in mice (5). In this issue of the JCI, Wiede and colleagues address this issue by generating mice in which Ptpn2 is conditionally deleted in T cells (4). Analysis of these mice has unmasked a cell-intrinsic function for TCPTP as a negative regulator of TCR signaling (Figure ​(Figure1).1). Using substrate-trap mutants of TCPTP, Wiede and colleagues identified the T cell SFKs Lck and Fyn as direct substrates of TCPTP, although the mechanism by which the predominantly nuclear TCPTP is recruited to the membrane-associated SFKs remains to be determined. SFKs are critical mediators of TCR signaling and are themselves tightly regulated by inhibitory and activation loop tyrosine phosphorylation (12). By dephosphorylating the activation loop tyrosine of the SFKs, TCPTP presumably inhibits SFK enzymatic activity and thereby impairs TCR signaling. Wiede and colleagues found that in vitro, TCPTP-deficient T cells exhibited enhanced activation and proliferation upon TCR stimulation (4). In vivo, conditional deletion of TCPTP in T cells was found to drive enhanced TCR-dependent selection of T cells in the thymus and accumulation of memory phenotype T cells in the periphery. Importantly, regulatory Foxp3⁺ T cells, critical suppressors of systemic autoimmunity, were unperturbed. Taken together, these observations of Wiede and colleagues suggest that an altered threshold for T cell activation may contribute to abnormal T cell homeostasis in the T cell–specific TCPTP-deficient mice. However, TCPTP is a critical negative regulator of JAK/STAT signaling pathways downstream of cytokines such as IL-2, which has an important function in T cell activation (2, 7, 8). Therefore, it remains possible that abnormal T cell homeostasis in these mice is not driven exclusively by dysregulated TCR signaling (Figure ​(Figure1). 1).

The conditional T cell deletion of Ptpn2 reported by Wiede and colleagues (4) suggests that dysregulated TCR signaling may contribute to autoimmunity in patients harboring disease-associated PTPN2 SNPs (1–3). Although Wiede et al. did not directly probe this pathway in patient samples, the TCR signaling pathway has been previously implicated in autoimmune disease pathogenesis by GWAS (13). A particularly well-studied and relevant example is the PTPN22 gene, which encodes Lyp (murine ortholog, Pep), a hematopoietically expressed cytoplasmic tyrosine phosphatase that is structurally unrelated to TCPTP. A single coding SNP in this gene (PTPN22 C1858T) has been associated with multiple autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes (1, 14–16). Lyp/Pep, like TCPTP, negatively regulates TCR signaling, at least in part by dephosphorylating the activation loop tyrosine of SFKs (17). Indeed, Pep-deficient mice recapitulate a subset of phenotypes identified by Wiede and colleagues in their T cell–specific TCPTP-deficient mice (4), including enhanced thymic positive selection, accumulation of effector/memory phenotype T cells, and enhanced spontaneous germinal center formation (18). However, the disease that develops spontaneously in the T cell–specific TCPTP-deficient mice does not occur in Pep-deficient mice. This may be due to the distinct potency and temporal requirement of the two phosphatases during TCR signaling. Alternatively, this may suggest that dysregulation of cytokine signaling pathways in T cell–specific TCPTP-deficient mice contribute to late-onset inflammatory disease.

Mouse and human data suggest that reduced expression of TCPTP might drive human autoimmune disease by enhancing signaling downstream of the TCR, cytokines, or growth factors to produce a proinflammatory cytokine milieu (2, 4, 5, 10, 11). Importantly, disease may reflect abnormalities in immune cell development as well as mature immune cell function. Because TCPTP is ubiquitously expressed and regulates multiple signaling pathways, dissecting the functional consequences of human SNPs in the gene encoding this protein will be challenging.