ReviewRoles of the protein tyrosine phosphatase PTPN22 in immunity and autoimmunity
Introduction
The PTPN22 allele C1858T corresponds to the single amino acid substitution R620W (arginine to tryptophan), which is associated with several organ-specific and systemic autoimmune diseases [1], [2], [3], [4], [5]. Interestingly, this allele is not associated with multiple sclerosis (MS) [6] or psoriasis [7], instead it increases the risk of several others, such as type 1 diabetes (T1D) [8], [9], [10], Hashimoto's thyroiditis [11], rheumatoid arthritis (RA) [12], [13], systemic lupus erythematosus (SLE) [14], vitiligo [15] and Grave's disease [16] (Fig. 1). Although greater in homozygous donors, autoimmune disease susceptibility affects heterozygous carriers too. The frequency of the PTPN22 R620W (PTPN22*W) polymorphism in the general population is usually very low, but in certain areas, such as Scandinavia, it can reach ~ 15% [13], [17]. Caucasian patients (of North American or European ancestors) with T1D, RA or SLE have been the subject of numerous PTPN22-centered genetic and functional studies, while the results of larger, ongoing analyses in other ethnic groups (African American, Asian and Hispanic) are underway. These new studies may shed light on what makes certain ethnic groups more susceptible to specific autoimmune diseases. For example, African American, Hispanic, Asian and Native American women are two to three times more likely to develop SLE than Caucasian women [18]. Therefore, studying the contribution of PTPN22*W (and other polymorphisms) across ethnic groups will advance our understanding of the geo-environmental underpinnings that contributed to the emergence of autoimmunity.
It is intriguing that the PTPN22*W variant predisposes to several yet not all autoimmune diseases. It has been estimated that about a dozen of specific genetic variations are cumulatively involved in disease pathogenesis. Thus, PTPN22 might increase susceptibility when combined with other genetic polymorphisms. In addition to this gene–gene effect, other factors e.g., gene–environment interactions (epigenetics) are also considered essential in determining autoimmune disease pathogenesis (for review please refer to [19], [20]). PTPN22*W seems to affect autoimmune diseases that share a strong innate and B-cell component such as SLE and T1D but not MS. As such, this association has spurred attempts to identify the common pathophysiological mechanisms that might be triggered by the presence of the PTPN22*W allele. Autoantibody production seems the major shared pathophysiological mechanism, depicted in Fig. 2.
PTPN22 encodes for LYP [21], a protein tyrosine phosphatase (PTP); the mouse homolog of LYP is PEP (PEST domain-enriched tyrosine phosphatase) [22], [23]. LYP is considered a powerful inhibitor of T-cell activation and contributes to signaling cascades initiated in several types of immune cells, including B cells and cells of the innate immune system. Several experimental differences, that have not yet been reconciled, generated a lot of confusion regarding the function of the PTPN22*W variant in immunity and autoimmunity. Most studies indicate that PTPN22*W represents a gain-of-function allele while others support the notion that this allele has reduced activity (loss-of function). This review attempts to: summarize current knowledge regarding PTPN22, describe its role in human and murine innate and adaptive immune responses, provide possible explanations for numerous conflicting findings, and suggest new lines of research.
Section snippets
PTPN22 in innate immune cells
Autoimmune diseases are characterized by a large number of functional abnormalities in immune cells whose description goes far beyond the scope of this review. PTPN22 is expressed by many immune cells. The results of gene expression studies lodged in the BioGPS bank (http://biogps.org) show that CD4+ and CD8+ T cells, B cells, dendritic cells (DCs) and monocytes express PTPN22 at differing levels and, importantly, that natural killer (NK) cells express the highest PTPN22 mRNA levels in both
PTPN22 in T regulatory (Treg) cells and T helper differentiation
PTPN22 contains one N-terminal PTP domain and four prolin-rich motifs (P1–4) in the C-terminal region. The protein inhibits TCR signaling by dephosphorylating positive regulatory tyrosine residues in Src family kinases including ZAP-70 and LCK of the TCR signalosome. Interaction with the C-terminal Src kinase (CSK) through its P1 motif is important to exert its inhibitory activity. The PTPN22 R620W substitution is located in the P1 region that is essential for its association to CSK [37]. As
PTPN22 in conventional CD4+ and CD8+ T cells
Most PTPN22 knockout/knockdown models generated to date have demonstrated an accumulation of effector-memory CD4+ and CD8+ T-cells in the peripheral secondary lymphoid organs. This phenotype develops with age irrespective of genetic background. Furthermore, despite the increase in Treg cell numbers in some models, reduced levels of PTPN22 result in lymphadenopathy and splenomegaly [23], [36], [41]. Whether PTPN22 −/− memory T cells are pathogenic, and how they are controlled by PTPN22 −/− Treg
PTPN22 in B cells
Evidence regarding the role of PTPN22 in B cells also comes from studies in PTPN22-deficient and R619W KI mice. These mice develop spontaneous germinal centers (GCs) and have elevated serum antibodies, and can progress to systemic autoimmunity if crossed to CD45 E613R mice [46] or placed on a mixed genetic background, as previously mentioned [23]. Since B-cell development in the bone marrow appears to be normal, it has been suggested that this phenotype might be secondary to aberrant CD4+
Concluding remarks
Several epidemiological studies link the PTPN22 allele C1858T to human autoimmune diseases. However, the cellular and molecular mechanisms by which PTPN22*W contributes to disease development are not fully understood. Both T, B and myeloid cell functions seem to be affected, while its effect on other cell types, such as NK cells, still needs to be addressed. At the molecular level the activity of the phosphatase is enhanced, but unexpectedly, TCR and BCR signaling are predominantly increased.
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
Georgia Fousteri is supported by the European Union and the Juvenile Diabetes Research Foundation (JDRF). Manuela Battaglia is supported by the JDRF, the Italian Ministry of Health, and the European Union.
We would like to thank all the members of Manuela Battaglia's lab for their helpful and stimulating contributions.
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