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Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells.

ABSTRACT: Foxp3-expressing CD4⁺CD25⁺ regulatory T cells (Tregs) constitutively and highly express the immune checkpoint receptor cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), whose Treg-specific deficiency causes severe systemic autoimmunity. As a key mechanism of Treg-mediated suppression, Treg-expressed CTLA-4 down-regulates the expression of CD80/CD86 costimulatory molecules on antigen-presenting cells (APCs). Here, we show that Treg-expressed CTLA-4 facilitated Treg-APC conjugation and immune synapse formation. The immune synapses thus formed provided a stable platform whereby Tregs were able to deplete CD80/CD86 molecules on APCs by extracting them via CTLA-4-dependent trogocytosis. The depletion occurred even with Tregs solely expressing a mutant CTLA-4 form lacking the cytoplasmic portion required for its endocytosis. The CTLA-4-dependent trogocytosis of CD80/CD86 also accelerated in vitro and in vivo passive transfer of other membrane proteins and lipid molecules from APCs to Tregs without their significant reduction on the APC surface. Furthermore, CD80 down-regulation or blockade by Treg-expressed membrane CTLA-4 or soluble CTLA-4-immunoglobulin (CTLA-4-Ig), respectively, disrupted cis-CD80/programmed death ligand-1 (PD-L1) heterodimers and increased free PD-L1 on dendritic cells (DCs), expanding a phenotypically distinct population of CD80^lo free PD-L1^hi DCs. Thus, Tregs are able to inhibit the T cell stimulatory activity of APCs by reducing their CD80/CD86 expression via CTLA-4-dependent trogocytosis. This CD80/CD86 reduction on APCs is able to exert dual suppressive effects on T cell immune responses by limiting CD80/CD86 costimulation to naïve T cells and by increasing free PD-L1 available for the inhibition of programmed death-1 (PD-1)-expressing effector T cells. Blockade of CTLA-4 and PD-1/PD-L1 in combination may therefore synergistically hinder Treg-mediated immune suppression, thereby effectively enhancing immune responses, including tumor immunity.

SUBMITTER: Tekguc M

PROVIDER: S-EPMC8325248 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abatacept (ABA) is used as a first-line treatment in patients diagnosed with moderate and severe rheumatoid arthritis (RA). The interindividual response to ABA therapy is very variable in these patients. The objective of our study was therefore to investigate the role of polymorphisms of the CTLA-4, CD80 and CD86 genes, as well as that of clinical factors of the disease, in the response to ABA in patients with RA. A retrospective cohort study was carried out in 109 patients receiving treatment with ABA and diagnosed with RA. The genetic variables were analyzed using real-time PCR with TaqMan® probes. The patients were classified according to the European League Against Rheumatism (EULAR) criteria at 6 and 12 months from start of treatment. The independent variables associated with higher EULAR response were lower duration of previous biologic disease-modifying anti-rheumatic drugs and lower baseline values of the disease activity score 28 after 6 months of ABA treatment; and lower baseline patient's visual analogue scale (PVAS) after 12 months. In addition, a significant association was found between duration of ABA treatment, non-administration of concomitant glucocorticoids and lower baseline values of the number of inflamed joints and erythrocyte sedimentation rate clinical variables, with remission of the disease after 6 months' treatment with ABA. Finally, remission of the disease after 12 months' treatment with ABA was associated with earlier age at start of ABA therapy and lower number of previous biologic therapies (BTs). The CTLA-4rs5742909-T allele and the CTLA-4rs231775-G allele were found to be associated with satisfactory EULAR response and low disease activity (LDA) after 12 months' treatment with ABA (CTLA-4rs5742909 T vs. CC; OR = 5.88; CI95% = 1.48-23.29 and OR = 4.75; CI95% = 1.35-17.94, respectively, and CTLA-4rs231775 G vs. AA, OR = 3.48; CI95% = 1.20-10.09 and OR = 4.68; CI95% = 1.49-17.94, respectively). In conclusion, patients with RA treated with ABA showed better EULAR response and LDA rate when they had the CTLA-4 rs5742909-T or CTLA-4 rs231775-G polymorphisms; furthermore, this remission rate increased in patients that began ABA treatment earlier, those with a lower number of previous BTs and those with a lower PVAS value.

Project description:In this article we report that the M2 protein encoded by the vaccinia virus is secreted as a homo-oligomer by infected cells and binds two central costimulation molecules, CD80 (B7-1) and CD86 (B7-2). These interactions block the ligation of the two B7 proteins to both soluble CD28 and soluble cytotoxic T-lymphocyte associated protein 4 (CTLA4) but favor the binding of soluble PD-L1 to soluble CD80. M2L gene orthologues are found in several other poxviruses, and the B7-CD28/CTLA4 blocking activity has been identified for several culture supernatants of orthopoxvirus-infected cells and for a recombinant myxoma virus M2 protein homolog (i.e., Gp120-like protein, or Gp120LP). Overall, these data indicate that the M2 poxvirus family of proteins may be involved in immunosuppressive activities broader than the NF-κB inhibition already reported (R. Gedey, X. L. Jin, O. Hinthong, and J. L. Shisler, J Virol 80:8676-8685, 2006, https://doi.org/10.1128/JVI.00935-06). A Copenhagen vaccinia virus with a deletion of the nonessential M2L locus was generated and compared with its parental virus. This M2L-deleted vaccinia virus, unlike the parental virus, does not generate interference with the B7-CD28/CTLA4/PD-L1 interactions. Moreover, this deletion did not affect any key features of the virus (in vitro replication, oncolytic activities in vitro and in vivo, and intratumoral expression of a transgene in an immunocompetent murine model). Altogether, these first results suggest that the M2 protein has the potential to be used as a new immunosuppressive biotherapeutic and that the M2L-deleted vaccinia virus represents an attractive new oncolytic platform with an improved immunological profile.IMPORTANCE The vaccinia virus harbors in its genome several genes dedicated to the inhibition of the host immune response. Among them, M2L was reported to inhibit the intracellular NF-κB pathway. We report here several new putative immunosuppressive activities of M2 protein. M2 protein is secreted and binds cornerstone costimulatory molecules (CD80/CD86). M2 binding to CD80/CD86 blocks their interaction with soluble CD28/CTLA4 but also favors the soluble PD-L1-CD80 association. These findings open the way for new investigations deciphering the immune system effects of soluble M2 protein. Moreover, a vaccinia virus with a deletion of its M2L has been generated and characterized as a new oncolytic platform. The replication and oncolytic activities of the M2L-deleted vaccinia virus are indistinguishable from those of the parental virus. More investigations are needed to characterize in detail the immune response triggered against both the tumor and the virus by this M2-defective vaccinia virus.

Project description:BackgroundCytotoxic T lymphocyte-associated antigen-4-Ig (CTLA-4-Ig) competes with CD28 for binding CD80/CD86 on antigen-presenting cells (APCs) to limit T cell activation. B cells are believed to be important APCs in the pathogenesis of autoimmune diseases and express CD80/CD86 after activation; however, relatively little is known about the effect of CTLA-4-Ig on B cells. This study tested the impact of CTLA-4-Ig on human B cell responses.MethodsHuman blood B cells were purified from healthy donors and activated in the presence of CTLA-4-Ig or the L6-Ig control protein in vitro. RT-q-PCR and immunofluorescence staining were performed to detect activation marker expression. ELISA was conducted to measure cytokine secretion. The CD80/CD86 levels on the surface of the memory B cells in the blood of 18 patients with rheumatoid arthritis (RA) were detected using immunofluorescence staining.ResultsCTLA-4-Ig suppressed the expression of Staphylococcus aureus (SAC)-induced CD80, CD86, TNFA, and IL6 in human B cells at the transcriptional level. Furthermore, CTLA-4-Ig concomitantly decreased SAC-induced CD80/CD86 surface expression on and TNF-α and IL-6 secretion from B cells. On the other hand, T cell-dependent (TD) stimulation-induced B cell activation, proliferation, plasma cell differentiation, and antibody secretion were not affected by CTLA-4-Ig. As expected, TD stimulation-induced surface CD80 was hindered by CTLA-4-Ig. Notably, a blockade of CD80/CD86 on the surface of the memory B cells was observed in the patients with RA after abatacept (CTLA-4-Ig) treatment. In a portion of the RA patients, restoration of CD80/CD86 staining on the surface of the memory B was detected starting in the 3rd month of abatacept treatment. Interestingly, the surface levels of CD80/CD86 on the patients' memory B cells positively correlated with disease activity.ConclusionsWe found that CTLA-4-Ig directly suppressed SAC-induced B cell activation in vitro. Obstruction of CD80 and CD86 on the surface of the memory B cells was detected in the RA patients after abatacept treatment. Blocking CD80/CD86 on B cells by CTLA-4-Ig may hinder T cell activation and associated with the disease activity of RA in vivo. Our findings indicate that CTLA-4-Ig may regulate humoral responses by modulating B cell activation and interfering T cell-B cell interaction.

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Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells.

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