Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity

Svensson, Mattias; Doody, Karen M.; Schmiedel, Benjamin Joachim; Bhattacharyya, Sourya; Panwar, Bharat; Wiede, Florian; Yang, Shen K.; Santelli, Eugenio; Wu, Dennis J.; Sacchetti, Cristiano; Gujar, Ravindra; Seumois, Grégory; Kiosses, William B.; Aubry, Isabelle; Kim, Gisen; Mydel, Piotr; Sakaguchi, Shimon; Kronenberg, Mitchell; Tiganis, Tony; Tremblay, Michel L.; Ay, Ferhat; Vijayanand, Pandurangan; Bottini, Nunzio

doi:10.1172/jci123267

Cited by 51 publications

(67 citation statements)

References 53 publications

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“…Additionally, the utilization of banked CB units avoids the necessity for large blood draws or leukapheresis procedures to obtain sufficient Treg quantities for expansion. This would be highly desirable in pediatric and autoimmune subjects, many of whom may exhibit lymphopenia, increased inflammatory cell populations as potential contaminants, or express multiple genetic susceptibility alleles that may negatively affect Treg function (127)(128)(129).…”

Section: Discussionmentioning

confidence: 99%

Human Regulatory T Cells From Umbilical Cord Blood Display Increased Repertoire Diversity and Lineage Stability Relative to Adult Peripheral Blood

et al. 2020

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Tregs. Interestingly, expression of canonical Treg markers, such as FOXP3, TIGIT, and IKZF2, were increased in CB CD4 + CD127 + conventional T cells (Tconv) compared to APB Tconv, post-expansion, implying perinatal T cells may adopt a default regulatory program. Collectively, these data identify surface markers (namely CXCR3) that could be depleted to improve purity and stability of APB Tregs, and support the use of expanded CB Tregs as a potentially optimal ACT modality for the treatment of autoimmune and inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Human Regulatory T Cells From Umbilical Cord Blood Display Increased Repertoire Diversity and Lineage Stability Relative to Adult Peripheral Blood

et al. 2020

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“…Injection of a mixture of cell‐depleting/blocking anti‐CD25 Abs to deplete Treg cells or inhibit Treg function evoked arthritis in SLAP −/− SKG mice, indicating that SLAP‐deficient Treg cells were protecting the mice from arthritis development. On the other hand, Treg‐specific reduced expression of phosphatase PTPN2, whose genetic polymorphism is highly associated with RA and inflammatory disease, attenuated Treg suppression, enhancing arthritis development in SKG mice …”

Section: Autoimmunity Caused By Impaired Tcr‐proximal Signalingmentioning

confidence: 99%

Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis

Takeuchi

Hirota

Sakaguchi

2020

Immunological Reviews

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Mutations of the genes encoding T‐cell receptor (TCR)‐proximal signaling molecules, such as ZAP‐70, can be causative of immunological diseases ranging from T‐cell immunodeficiency to T‐cell–mediated autoimmune disease. For example, SKG mice, which carry a hypomorphic point mutation of the Zap‐70 gene, spontaneously develop T‐cell–mediated autoimmune arthritis immunopathologically similar to human rheumatoid arthritis (RA). The Zap‐70 mutation alters the sensitivity of developing T cells to thymic positive/negative selection by self‐peptides/MHC complexes, shifting self‐reactive TCR repertoire to include a dominant arthritogenic specificity and also affecting thymic development and function of autoimmune suppressive regulatory T (Treg) cells. Polyclonal self‐reactive T cells, including potentially arthritogenic T cells, thus produced by the thymus recognize self‐peptide/MHC complexes on antigen‐presenting cells (APCs) in the periphery and stimulate them to produce cytokines including IL‐6 to drive the arthritogenic T cells to differentiate into arthritogenic T‐helper 17 (Th17) cells. Insufficient Treg suppression or activation of APCs via microbial and other environmental stimuli evokes arthritis by activating granulocyte‐macrophage colony‐stimulating factor‐secreting effector Th17 cells, mediating chronic bone‐destructive joint inflammation by activating myeloid cells, innate lymphoid cells, and synoviocytes in the joint. These findings obtained from the study of SKG mouse arthritis are instrumental in understanding how arthritogenic T cells are produced, become activated, and differentiate into effector T cells mediating arthritis, and may help devising therapeutic measures targeting autoimmune pathogenic Th17 cells or autoimmune‐suppressing Treg cells to treat and prevent RA.

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“…As mentioned, human disease-associated variants of PTPN2 only induce a partial loss of PTPN2 ( 32 ), which can be modeled by studying Ptpn2 -haploinsufficient mice ( 44 , 45 ). When compared with the dramatic phenotypes observed in Ptpn2 -deficient animals, Ptpn2 -haploinsufficient mice remain healthy under normal conditions ( 37 , 38 ), but in the presence of inflammatory triggers or when combined with other autoimmune disease–predisposing genes, they can develop gut or joint inflammation ( 44 , 45 ). This observation is consistent with the idea that disease-associated variants of PTPN2 need to interact with other risk factors to induce disease in humans.…”

Section: Introductionmentioning

confidence: 99%

“…Th17 cells are also considered key players in the pathogenesis of RA ( 47 – 49 ). Tregs’ conversion into FoxP3 – IL-17 + exTregs is thought to contribute to the generation of highly autoreactive IL-17 + effector T cells in RA ( 44 , 50 , 51 ). We recently showed that Ptpn2 haploinsufficiency, which models the loss of PTPN2 expression observed in carriers of PTPN2 risk alleles for IBD and RA, enhances development of Th17-dependent arthritis when introduced onto the SKG mouse background.…”

Section: Introductionmentioning

confidence: 99%

“…We recently showed that Ptpn2 haploinsufficiency, which models the loss of PTPN2 expression observed in carriers of PTPN2 risk alleles for IBD and RA, enhances development of Th17-dependent arthritis when introduced onto the SKG mouse background. We identified a novel Treg-intrinsic mechanism for PTPN2 in maintaining peripheral Treg stability during arthritic inflammation and limiting the generation of highly arthritogenic exTregs ( 44 ).…”

Section: Introductionmentioning

confidence: 99%

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PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis

Hsieh¹,

Svensson²,

Zoccheddu³

et al. 2020

JCI Insight

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Loss-of-function variants of protein tyrosine phosphatase non-receptor type 2 ( PTPN2 ) enhance risk of inflammatory bowel disease and rheumatoid arthritis; however, whether the association between PTPN2 and autoimmune arthritis depends on gut inflammation is unknown. Here we demonstrate that induction of subclinical intestinal inflammation exacerbates development of autoimmune arthritis in SKG mice. Ptpn2 -haploinsufficient SKG mice — modeling human carriers of disease-associated variants of PTPN2 — displayed enhanced colitis-induced arthritis and joint accumulation of Tregs expressing RAR-related orphan receptor γT (RORγt) — a gut-enriched Treg subset that can undergo conversion into FoxP3 – IL-17 + arthritogenic exTregs. SKG colonic Tregs underwent higher conversion into arthritogenic exTregs when compared with peripheral Tregs, which was exacerbated by haploinsufficiency of Ptpn2 . Ptpn2 haploinsufficiency led to selective joint accumulation of RORγt-expressing Tregs expressing the colonic marker G protein–coupled receptor 15 (GPR15) in arthritic mice and selectively enhanced conversion of GPR15 + Tregs into exTregs in vitro and in vivo. Inducible Treg-specific haploinsufficiency of Ptpn2 enhanced colitis-induced SKG arthritis and led to specific joint accumulation of GPR15 + exTregs. Our data validate the SKG model for studies at the interface between intestinal and joint inflammation and suggest that arthritogenic variants of PTPN2 amplify the link between gut inflammation and arthritis through conversion of colonic Tregs into exTregs.

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Reduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunity

Cited by 51 publications

References 53 publications

Human Regulatory T Cells From Umbilical Cord Blood Display Increased Repertoire Diversity and Lineage Stability Relative to Adult Peripheral Blood

Human Regulatory T Cells From Umbilical Cord Blood Display Increased Repertoire Diversity and Lineage Stability Relative to Adult Peripheral Blood

Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis

PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis

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