T Cell Activation Regulates CD6 Alternative Splicing by Transcription Dynamics and SRSF1

Glória, Vânia G. da; Araújo, Mafalda; Santos, Ana Mafalda; Leal, Rafaela; Almeida, Sérgio Fernandes de; Carmo, Alexandre M.; Moreira, Alexandra

doi:10.4049/jimmunol.1400038

Cited by 26 publications

(18 citation statements)

References 69 publications

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“…Further, we report that in Th17 pol conditions the median expression and absolute receptor counts for CD6 on T-cells are increased even further than when stimulated in Thnp condition (Fig 1D and 1E). While the increased expression of CD6 under PMA stimulation [67] and the increased mRNA expression in PHA stimulated PBMC [68] has been reported, to our knowledge this is the first time that the increased expression of CD6 receptor in vitro under a TCR mediated stimulation along with co-stimulation has been quantified.…”

Section: Discussionmentioning

confidence: 98%

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

et al. 2017

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CD6 is associated with T-cell modulation and is implicated in several autoimmune diseases. We previously demonstrated that Itolizumab, a CD6 domain 1 (CD6D1) specific humanized monoclonal antibody, inhibited the proliferation and cytokine production by T lymphocytes stimulated with anti-CD3 antibody or when co-stimulated with ALCAM. Aberrant IL-17 producing CD4+ helper T-cells (Th17) have been identified as pivotal for the pathogenesis of certain inflammatory autoimmune disorders, including psoriasis. Itolizumab has demonstrated efficacy in human diseases known to have an IL-17 driven pathogenesis. Here, in in vitro experiments we show that by day 3 of human PBMC activation using anti-CD3 and anti-CD28 co-stimulation in a Th17 polarizing milieu, 15–35% of CD4+ T-cells overexpress CD6 and there is an establishment of differentiated Th17 cells. Addition of Itolizumab reduces the activation and differentiation of T cells to Th17 cells and decreases production of IL-17. These effects are associated with the reduction of key transcription factors pSTAT3 and RORγT. Further, transcription analysis studies in these conditions indicate that Itolizumab suppressed T cell activation by primarily reducing cell cycle, DNA transcription and translation associated genes. To understand the mechanism of this inhibition, we evaluated the effect of this anti-human CD6D1 mAb on ALCAM-CD6 as well as TCR-mediated T cell activation. We show that Itolizumab but not its F(ab’)2 fragment directly inhibits CD6 receptor hyper-phosphorylation and leads to subsequent decrease in associated ZAP70 kinase and docking protein SLP76. Since Itolizumab binds to CD6 expressed only on human and chimpanzee, we developed an antibody binding specifically to mouse CD6D1. This antibody successfully ameliorated the incidence of experimental autoimmune encephalitis in the mice model. These results position CD6 as a key molecule in sustaining the activation and differentiation of T cells and an important target for modulating autoimmune diseases.

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Section: Discussionmentioning

confidence: 98%

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

et al. 2017

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“…Conversely, the function of CD6 in lymphocyte biology is controversial, playing a bimodal role as described recently . Thus, while the T cell‐activating properties of CD6 depend upon binding to CD166, its inhibitory effects have been shown to be independent of the interaction with this ligand.…”

Section: Discussionmentioning

confidence: 99%

The anti-CD6 antibody itolizumab provides clinical benefit without lymphopenia in rheumatoid arthritis patients: results from a 6-month, open-label Phase I clinical trial

Rodríguez

Prada²,

Moreno

et al. 2017

Clinical and Experimental Immunology

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Itolizumab is a humanized anti-CD6 monoclonal antibody (mAb) that has previously shown encouraging results, in terms of safety and positive clinical effects, in a 6-week monotherapy clinical trial conducted in rheumatoid arthritis (RA) patients. The current Phase I study evaluated the safety and clinical response for a longer treatment of 12 itolizumab intravenous doses in subjects with active RA despite previous disease-modifying anti-rheumatic drug (DMARD) therapy. Twenty-one subjects were enrolled into four dosage groups (0·1, 0·2, 0·4 and 0·8 mg/kg). Efficacy end-points including American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates and disease activity score in 28 joints (DAS28) were monitored at baseline and at specific time-points during a 10-week follow-up period. Itolizumab was well tolerated up to the highest tested dose. No related serious adverse events were reported and most adverse events were mild. Remarkably, itolizumab treatment did not produce lymphopenia and, therefore, was not associated with infections. All patients achieved a clinical response (ACR20) at least once during the study. Eleven subjects (55%) achieved at least a 20% improvement in ACR just 1 week after the first itolizumab administration. The clinical response was observed from the beginning of the treatment and was sustained during 24 weeks. The efficacy profile of this 12-week treatment was similar to that of the previous study (6-week treatment). These results reinforce the safety profile of itolizumab and provide further evidence on the clinical benefit from the use of this anti-CD6 mAb in RA patients.

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“…Studies in Caucasians demonstrated a significant association of the G allele of rs17824933 in CD6 with MS risk 12 , although this could not be confirmed in Korean patients 24 . The MS risk allele in the rs17824933 CD6 locus may result in an alternative splicing of the gene 41 and this locus has been found to affect proliferation of CD4 (+) T cells 42 .…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms of cell adhesion molecules in Behcet’s disease in a Chinese Han population

Zheng

Zhang

et al. 2016

Sci Rep

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Cell adhesion molecules (CAMs) are involved in various immune-mediated diseases. This study was conducted to investigate the association of single nucleotide polymorphisms (SNPs) of CAMs with Behçet’s disease (BD) in a Chinese Han population. A two-stage association study was carried out in 1149 BD patients and 2107 normal controls. Genotyping of 43 SNPs was performed using MassARRAY System (Sequenom), polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and TaqMan SNP assays. The expression of CD6 and CD11c was examined by real-time PCR and cytokine production was measured by ELISA. A significantly higher frequency of the CT genotype, and a lower frequency of the CC genotype and C allele of CD6 rs11230563 were observed in BD as compared with controls. Analysis of CD11c rs2929 showed that patients with BD had a significantly higher frequency of the GG genotype and G allele, and a lower frequency of the AG genotype as compared with controls. Functional experiments showed an increased CD11c expression and increased production of TNF-α and IL-1beta by LPS stimulated PBMCs in GG carriers of CD11c rs2929 compared to AA/AG carriers. Our study provides evidence that CD6 and CD11c are involved in the susceptibility to BD in a Chinese Han population.

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T Cell Activation Regulates CD6 Alternative Splicing by Transcription Dynamics and SRSF1

Cited by 26 publications

References 69 publications

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab

The anti-CD6 antibody itolizumab provides clinical benefit without lymphopenia in rheumatoid arthritis patients: results from a 6-month, open-label Phase I clinical trial

Genetic polymorphisms of cell adhesion molecules in Behcet’s disease in a Chinese Han population

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