Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature

Çağdaş, Deniz; Halaçlı, Sevil Oskay; Tan, Çağman; Esenboğa, Saliha; Karaatmaca, Betül; Çetinkaya, Pınar Gür; Balcı-Hayta, Burcu; Ayhan, A.; Üner, Ayşegül; Orhan, Dıclehan; Boztuğ, Kaan; Özen, Seza; Topaloğlu, Rezan; Sanal, Özden; Tezcan, İlhan

doi:10.1016/j.jaip.2021.05.032

Cited by 17 publications

(33 citation statements)

References 48 publications

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“…These included two patients with previously unidentified STK4 frameshift mutations (c.1103delT and c.1245delA), two other siblings with a previously reported deep intronic mutation (c.1362+28,055A>G) and one patient with a premature stop codon (c.1399c>T) (Fig. 7A) ( 18 ). Results revealed evidence of immune dysregulation in the patients with decreased frequencies of naïve (CD4 + CD45RA + CCR7 + ) and central memory (CD4 + CD45RA − CCR7 + ) T reg and T eff cells and increased frequencies of effector memory (CD4 + CD45RA − CCR7 − ) T reg and T eff cells, whereas those of CD4 + CD45RA + CCR7 − terminally differentiated effector memory T reg and T eff cells were unchanged (Fig.…”

Section: Resultsmentioning

confidence: 99%

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A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T _reg cell activation and homeostasis

et al. 2022

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The molecular programs involved in regulatory T (T reg ) cell activation and homeostasis remain incompletely understood. Here, we show that T cell receptor (TCR) signaling in T reg cells induces the nuclear translocation of serine/threonine kinase 4 (Stk4), leading to the formation of an Stk4–NF-κB p65–Foxp3 complex that regulates Foxp3- and p65-dependent transcriptional programs. This complex was stabilized by Stk4-dependent phosphorylation of Foxp3 on serine-418. Stk4 deficiency in T reg cells, either alone or in combination with its homolog Stk3, precipitated a fatal autoimmune lymphoproliferative disease in mice characterized by decreased T reg cell p65 expression and nuclear translocation, impaired NF-κB p65–Foxp3 complex formation, and defective T reg cell activation. In an adoptive immunotherapy model, overexpression of p65 or the phosphomimetic Foxp3 S418E in Stk3/4-deficient T reg cells ameliorated their immune regulatory defects. Our studies identify Stk4 as an essential TCR-responsive regulator of p65-Foxp3–dependent transcription that promotes T reg cell–mediated immune tolerance.

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Section: Resultsmentioning

confidence: 99%

“…Patients with global STK4 deficiency suffer from recurrent infections, immune dysregulation, and autoimmunity (8,(16)(17)(18). Studies in mice have revealed different roles for Stk3/4 in T cell and dendritic cell responses (19,20).…”

Section: Introductionmentioning

confidence: 99%

A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T _reg cell activation and homeostasis

et al. 2022

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“…Serine/threonine kinase 4 deficiency is an autosomal recessive PID, which is characterized by a profoundly decreased level of CD4+ T cells, with a tendency toward viral and bacterial infections and mucocutaneous candidiasis. 1,2 As HSCT is a curative treatment approach in PIDs, it can be inferred that this could also be applicable in STK4-deficient patients. However, there are actually more than 300 single-gene mutations that have been identified that result in PID, and not all may be appropriate for HSCT.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic stem cell transplantation in serine/threonine kinase 4 (STK4) deficiency: Report of two cases and literature review

Uygun

Keleş

Daloğlu

et al. 2022

Pediatric Transplantation

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Background: Serine/threonine kinase 4 (STK4) deficiency is a combined immunodeficiency (CID) characterized by early onset recurrent bacterial, viral, and fungal infections. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for CID; however, little is known about the necessity and benefits of HSCT in patients with STK4 deficiency. Methods:We report two siblings with STK4 deficiency transplanted from two unrelated donors with the same conditioning regimen. Results:In the conditioning regimen, rituximab was given on Day −11 (375 mg/m 2 ), and sirolimus was added on the same day. Busulfan was administered at a myeloablative dose (3.2 mg/kg; Days −7 to −4) with 150 mg/m 2 of fludarabine (Days −7 to −3).They were transplanted with peripheral blood stem cells, and graft-versus-host disease (GVHD) prophylaxis was administered with 10 mg/m 2 methotrexate on Days 1, 3, and 6. In addition, mycophenolate mofetil (MMF) was started on Day 1 with ongoing use of sirolimus. We did not encounter veno-occlusive disease (VOD), high-grade acute GVHD, or significant organ toxicity in either patient. Both patients were well at the end of the first year after HSCT with complete donor chimerism.Conclusions: Serine/threonine kinase 4 deficiency is a disease with high mortality post-HSCT; therefore, the conditioning regimen and GVHD prophylaxis strategies are important considerations in these patients. In our opinion, the conditioning regimen, which includes rituximab and busulfan and fludarabine (BU-FLU), GVHD prophylaxis with sirolimus and MMF, and short-term methotrexate, offers favorable outcomes and is well tolerated in our STK4-deficient patients.

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“…Notably, another group of T-cell immunodeficiencies (not reviewed here), is characterized by the loss of naive T cells due to survival defects and/or abnormalities in lymphocyte cytoskeleton remodeling, migration or immunological synapse formation. These immunodeficiencies that include DOCK8, MST1/STK4, WASP and CORO1A deficiencies lead to severe defects in T cell responses [ [102] , [103] , [104] , [105] ].…”

Section: Conclusive Remarksmentioning

confidence: 99%

Inherited immunodeficiencies associated with proximal and distal defects in T cell receptor signaling and co-signaling

Latour

2022

Biomedical Journal

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Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature

Cited by 17 publications

References 48 publications

A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T _reg cell activation and homeostasis

A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T _reg cell activation and homeostasis

Hematopoietic stem cell transplantation in serine/threonine kinase 4 (STK4) deficiency: Report of two cases and literature review

Inherited immunodeficiencies associated with proximal and distal defects in T cell receptor signaling and co-signaling

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Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature

Cited by 17 publications

References 48 publications

A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T reg cell activation and homeostasis

A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T reg cell activation and homeostasis

Hematopoietic stem cell transplantation in serine/threonine kinase 4 (STK4) deficiency: Report of two cases and literature review

Inherited immunodeficiencies associated with proximal and distal defects in T cell receptor signaling and co-signaling

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Product

Resources

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A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T _reg cell activation and homeostasis

A Stk4-Foxp3–NF-κB p65 transcriptional complex promotes T _reg cell activation and homeostasis