CD101 genetic variants modify regulatory and conventional T cell phenotypes and functions

Richert-Spuhler, Laura E.; Mar, Corinne M.; Shinde, Paurvi; Wu, Feinan; Hong, Ting; Greene, Evan; Hou, Sharon; Thomas, Katherine K.; Gottardo, Raphaël; Bruyn, Guy de; Celum, Connie; Baeten, Jared M.; Lingappa, Jairam R.; Lund, Jennifer M.; Wald, Anna; Campbell, Mary S.; Corey, Lawrence; Coombs, Robert W.; Magaret, Amalia; McElrath, M. Juliana; Morrow, Rhoda; Mullins, James I.; Coetzee, David; Fife, Kenneth H.; Were, Edwin; Essex, Max; Makhema, Joseph; Katabira, Elly; Ronald, Allan R.; Bukusi, Elizabeth A.; Cohen, Craig R.; Kapiga, Saidi; Manongi, Rachel; Farquhar, Carey; John‐Stewart, Grace; Kiarie, James; Delany‐Moretlwe, Sinead; Rees, Helen; Gray, Glenda; McIntyre, James; Mugo, Nelly; Donnell, Deborah; Frenkel, Lisa M.; Hendrix, Craig W.; Tumwesigye, Elioda; Ndase, Patrick; Bukusi, Eliabeth; Wangisi, Jonathan; Campbell, James D.; Tappero, Jordan W.

doi:10.1016/j.xcrm.2021.100322

Cited by 7 publications

(6 citation statements)

References 37 publications

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“…Differential protein analysis of immature naive B cells comparing treatment-naive JDM to HC identified increased expression of CD325 and MICA-MICB and decreased expression of CD1C, BAFF-R and PD-L1 (Supplemental Table 1). Within the CD4 + T compartment (Supplemental Figure 3A), CD4 + Tregs from TNJDM had higher expression of Tim-3, ICOS, CD164 and CD38 and down-regulation of CD101, a molecule which decreases pro-inflammatory T cell responses (28). CD4 + Teff in patients with treatment-naive JDM had higher surface expression of CD164 and PD-1 and down regulation of KLRG1, an inhibitory molecule (Supplemental Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics

Rabadam,

Wibrand,

Flynn

et al. 2023

Preprint

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Juvenile Dermatomyositis (JDM) is one of several childhood-onset autoimmune disorders characterized by a type I interferon response and autoantibodies. Treatment options are limited due to incomplete understanding of how the disease emerges from dysregulated cell states across the immune system. We therefore investigated the blood of JDM patients at different stages of disease activity using single-cell transcriptomics paired with surface protein expression. By immunophenotyping peripheral blood mononuclear cells, we observed skewing of the B cell compartment towards an immature naive state as a hallmark of JDM. Furthermore, we find that these changes in B cells are paralleled by signatures of Th2-mediated inflammation. Additionally, our work identified SIGLEC-1 expression in monocytes as a composite measure of heterogeneous type I interferon activity in disease. We applied network analysis to reveal that hyperactivation of the type I interferon response in all immune populations is coordinated with dysfunctional protein processing and regulation of cell death programming. This analysis separated the ubiquitously expressed type I interferon response into a central hub and revealed previously masked cell states. Together, these findings reveal the coordinated immune dysregulation underpinning JDM and provide novel insight into strategies for restoring balance in immune function.

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Section: Resultsmentioning

confidence: 99%

Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics

Rabadam,

Wibrand,

Flynn

et al. 2023

Preprint

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“…Moreover, TAMs were capable of releasing various inhibitory cytokines that further impaired antitumor functions of T cells ( 6 , 39 , 40 ). Based on a functional network and literature related to CD101 ( 10 , 13 , 41 ), we found that CD101 might have a close relationship with multiple functional markers of T cells, including CD8A, CD4, CD3G, IL2, and FOXP3. Furthermore, enrichment analysis based on CD101 proteins revealed that CD101 is potentially involved in the biological processes related to T cell immune response and antigen presentation.…”

Section: Discussionmentioning

confidence: 97%

“…Previous studies have demonstrated that the CD101 gene encodes a transmembrane glycoprotein predominantly expressed on dendritic cells, monocytes, and T cells ( 8 ). Of note, recent work of CD101 mainly focused on its role in restraining T cells in inflammatory processes including infectious ( 9 , 10 ) and autoimmunity diseases ( 11 , 12 ). CD101 was demonstrated to exert a potent effect on dampening T cell proliferation and activation in a TCR/CD3-dependent manner, as supported by the suppressed expression of IL-2RA and diminished secretion of IL-2 ( 8 , 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, CD101 was characterized as one of the hallmarks of T cell anergy ( 15 ). Likewise, CD101 variants can also alter the function of T cells by mediating Treg cell dysfunction and increasing T cell activation, thereby contributing to the homeostatic regulation of inflammation ( 10 ). Nevertheless, as a molecule expressed on diverse immune cell populations, the role of CD101 in many other cell types and human diseases remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Identification of CD101 in Glioma: A Novel Prognostic Indicator Expressed on M2 Macrophages

et al. 2022

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Glioma represents the most common primary intracranial malignancy worldwide, with low overall survival rates and limited therapeutic options. The protein CD101, mainly expressed on several immune cells, has been demonstrated to exert potent effects on blunting T cell immune responses across infectious and autoimmunity diseases. Nevertheless, the prognostic value of CD101 expression and its role in the immune microenvironment of various malignancies currently remains elusive. Herein, by adopting bioinformatics methodology, we comprehensively illustrated the potential function and predictive value of CD101 in stratifying clinical prognosis among patients with glioma, for which a high CD101 level predicted an unfavorable clinical outcome in glioma patients. Results from enrichment analyses manifested that CD101 predominantly expressed on the tumor-associated macrophages and was significantly associated with the immune regulatory processes, as evidenced by its positive correlation with immune-related genes and the putative infiltration of immune cells. Evidence provided by in-situ multicolor immunofluorescence staining further validated our findings at the protein level. Taken together, CD101 may serve as a novel biomarker in predicting clinical prognosis and immune status for glioma patients.

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“…Unfortunately, given the very low levels of CD101 + CD4 T cells after infection, we are unable to sort these cells and directly assess whether they harbor more virus at this time. The idea that CD101 expression is associated with preferential infection and depletion is additionally supported by two independent studies in which genetic variants in the CD101 locus are associated with altered immune activation and increased risk of sexually acquired HIV infection [ 76 , 77 ]. While we did not find significant enrichment of HIV DNA in CD101 + cells from PBMC, we were unable to assess either LN and rectal biopsy samples for these measures, where we believe the impact of both preferential depletion of CD101 + CD4 T cells and the immunosuppressive environment created by them on ART may be most significant.…”

Section: Discussionmentioning

confidence: 99%

The role of CD101-expressing CD4 T cells in HIV/SIV pathogenesis and persistence

Strongin

Hoang²,

Tharp³

et al. 2022

PLoS Pathog

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Despite the advent of effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) continues to pose major challenges, with extensive pathogenesis during acute and chronic infection prior to ART initiation and continued persistence in a reservoir of infected CD4 T cells during long-term ART. CD101 has recently been characterized to play an important role in CD4 Treg potency. Using the simian immunodeficiency virus (SIV) model of HIV infection in rhesus macaques, we characterized the role and kinetics of CD101+ CD4 T cells in longitudinal SIV infection. Phenotypic analyses and single-cell RNAseq profiling revealed that CD101 marked CD4 Tregs with high immunosuppressive potential, distinct from CD101- Tregs, and these cells also were ideal target cells for HIV/SIV infection, with higher expression of CCR5 and α4β7 in the gut mucosa. Notably, during acute SIV infection, CD101+ CD4 T cells were preferentially depleted across all CD4 subsets when compared with their CD101- counterpart, with a pronounced reduction within the Treg compartment, as well as significant depletion in mucosal tissue. Depletion of CD101+ CD4 was associated with increased viral burden in plasma and gut and elevated levels of inflammatory cytokines. While restored during long-term ART, the reconstituted CD101+ CD4 T cells display a phenotypic profile with high expression of inhibitory receptors (including PD-1 and CTLA-4), immunsuppressive cytokine production, and high levels of Ki-67, consistent with potential for homeostatic proliferation. Both the depletion of CD101+ cells and phenotypic profile of these cells found in the SIV model were confirmed in people with HIV on ART. Overall, these data suggest an important role for CD101-expressing CD4 T cells at all stages of HIV/SIV infection and a potential rationale for targeting CD101 to limit HIV pathogenesis and persistence, particularly at mucosal sites.

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CD101 genetic variants modify regulatory and conventional T cell phenotypes and functions

Cited by 7 publications

References 37 publications

Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics

Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics

Identification of CD101 in Glioma: A Novel Prognostic Indicator Expressed on M2 Macrophages

The role of CD101-expressing CD4 T cells in HIV/SIV pathogenesis and persistence

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