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Development, Maintenance and Functions of CD8+ T-Regulatory Cells

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Chakraborty S, Sa G. J Immunol Sci. (2018); 2(2): 8-12 Journal of Immunological Sciences Minireview Open Access Development, maintenance and functions of CD8+ T-regulatory cells: Molecular orchestration of FOXP3 transcription Sreeparna Chakraborty1 & Gaurisankar Sa1* 1Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700054, India Article Info ABSTRACT Article Notes Modulation of immune cells to rejuvenate the immune responses Received: January 10, 2018 against cancer becomes a promising strategy for cancer therapy. T-regulatory Accepted: March 23, 2018 cells are one of the major hurdles in successful cancer immunotherapy. Recent + + *Correspondence: studies discovered that apart from CD4 Treg cells, CD8 Tregs also play roles in Prof. Gaurisankar Sa, Division of Molecular Medicine, Bose tumor immune evasion. Moreover, CD8+ Tregs shows synergistic immunosup- Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, pression with CD4+ Treg cells in tumor microenvironment. Several phenotypic Kolkata 700 054, India; markers have been described for peripherally induced CD8+ Treg cells, but Tel: +91-33-2569-3258; till now no universal phenotypic signature has yet established. FOXP3 is the Fax: +91-33-2355-3886, E-mail: [email protected] master regulator of Treg cells and its transcription is critically regulated by pro- © 2018 Sa G. This article is distributed under the terms of the moter region as well as three intronic conserved non-coding regions, viz; CNS Creative Commons Attribution 4.0 International License. 1, 2 and 3. In this review, we have described the transcriptional networking associated with the regulation of FOXP3 in tumor-CD8+ Treg cells along with Keywords: CD4+ nTreg and iTreg cells. Intervention of the intensive transcriptional machin- Cancer ery of FOXP3 regulation may aid to target Treg cells and thus could potentiate Immunotherapy Treg immunotherapy of cancer. FOXP3 Transcription Introduction A new tide in cancer therapy encourages the immunotherapy to become - vances several immunotherapeutic strategies are evolving which include cancera clinically vaccines, potential adoptive way totransfer fight against of ex vivo this activateddeadly disease. T and naturalIn recent killer ad cells, CART cell and administration of antibodies or recombinant proteins - ecules1 The tumor microenvironment is enriched with cancer-associated that could block the immune checkpoint pathways i.e. co-stimulatory mol . andfibroblasts, thereby myeloid-derived act as a self-check suppressor mechanism cells, to maintainand T- regulatory the peripheral (Treg) toler cells.- In normal physiology Treg cells are potent suppressors of effector T cells tumor-associated Treg cells have been related to poor prognosis in various cancersance and1 homeostaticThe predominance in immune of Treg response. cells in However,the tumor expanded microenvironment densities ofis found to be one of the main impediments to successful cancer immunother- . insusceptibility is to selective depletion of differentiated Treg along with apy. Therefore, one methodology for initiating compelling hostile to tumor or immune checkpoint blockade and these might unleash potent antitu- the activation of tumor-specific effector T cells by using cancer vaccine Till now the involvement of FOXP3-positive CD4+ Treg cells with the ad- vancementmor responses of cancer to make is well the establishedcurrent cancer2, 3 immunotherapy more effective. of CD8+ Treg cells in tumor immunomodulation was resurrected, in part, by the occurrence of this suppressor cells . inHowever, the tumor the microenvironmentinterest in the role along with CD4+ Treg cells. Page 8 of 12 Chakraborty S, Sa G. J Immunol Sci. Journal of Immunological Sciences CD8+ Treg cell: a new recruitment to T-regulatory cell is reported11 family CD8+CD25+FOXP3+ T cells is profound12 Moreover, the role of CD8+Foxp3+ . In multiple sclerosis the predominance13 and of CD8+ + . +FoxP3+CCL4 CD8+ Treg cells4 Treg in GVHD+14 (Graft-versus-host disease) In the 1970s Grehson et al. first reported the existence of LAG-3 (Lymphocyte-activation-gene-3)CD25 and helps to maintain. Tregs the are homeostasis, generally classified while iTregs as either arise ‘natural’ in the prevalence(Chemokine-ligand-4) of CD8+ Treg in inflammatory infectious diseases+ + or nTreg or ’inducible or iTreg’. The nTregs develop in the thymus cellsis already in ovarian documented. cancer whichRecent suppress advances the in researchanti-tumor suggest immune the nCD8+ Tregs share functional and phenotypic similarities with CCR7(C-C chemokine-receptor-type-715 and CD8+CD28 ) IL10 cells CD4periphery+ following stimulation from microenvironment.5 The in non-small cell lung carcinoma16 On the other hand, in prostate− for peripherally induced CD8+ Treg cells, till now no universal cancer,response viaCD8 TGFβ1+CD25 +andCD122 IFNg+FOXP3 production+ Tregs and express CTLA4, GITR and FOXP3 . However, + show their. suppressive functions via Toll- CD8+ Treg cells have been discussed in many autoimmune GITR(glucocorticoid-inducedwhereas CD8+CD25+FOXP3+ phenotypic emblem has yet established. The involvement of cellsTNFR-related in colon cancer protein) that inhibit CD417 + T cell proliferation and Th1 biology6 The predominance of suppressor CD8+CD28 CD56+ cytokinelike receptor-8 production (TLR8)18 Our signaling research reported the occurrence of cells,diseases, CD8 +inflammatoryCD11c+ cells diseasesand CD8 as+CD25 well+ Foxp3as in +transplantation Tregs −in RA CD8+CD25+FOXP3+ Treg cells in breast tumor microenvironment . , CD8+CD122+ and CD8+LAP+ . +/PD-119+/ 7-9 - in nature These CD8+ . (rheumatoid arthritis), CD8+CD28 T cells in Myasthenia( latency- gravis inFurther the tumor study microenvironment identified19 that thisto suppress subset theis CTLA4effector T cells associated-peptide)9,10 Treg in EAE (Experimental-− autoimmune- CD127 . Treg cells secrete IL10 and TGFβ encephalomyelitis) Figure: The transcription of FOXP3 in nTreg and tumor-Treg: an integrative model. Expression of the FOXP3 gene is controlled by promoter and several regulatory regions. Several transcription factors viz; RUNX3, NFAT, AP1, STAT5 associated with FOXP3-promoter activity. Three conserved non-coding sequences (CNS1, CNS2 and CNS3) have been identified. NFAT, AP1 and SMAD3 bind to CNS1, which are required for chromatin modification and FOXP3 induction during tumor-Treg cell differentiation. CNS2 region associated with FOXP3 maintainence by GATA3, RUNX1–CBFβ complex and FOXP3. CNS3 region activity asgined to nTreg cells by binding of NFκB and c-Rel. Page 9 of 12 Chakraborty S, Sa G. J Immunol Sci. Journal of Immunological Sciences + cells Treg showed synergistic immunosuppression along with CD4+ Tregproliferation cells which and functions.further emphasize Moreover, their it was importance observed thatin tumor CD8 , whereas CNS3 activity is profound in thymus-derived nTreg immune evasion cells. Upon TCR stimulation NFκB and c-Rel bind to the CNS3- 19 maintenanceresponsive elements of FOXP3 and expression induce inFOXP3 both nTregtranscription. and iTreg On cells the28 FOXP3: the ace. controller of Treg cell other hand, the CNS2 region is exclusively associated with the . The FOXP3 gene is found on the X chromosome and mutation with tumor-induced CD8+ as well as CD4+ or loss of function of FOXP3 leads to severe autoimmune or Research showed that CNS1 region is profoundly associated iTreg generation. master regulator of Treg cells and the stable FOXP3 expression The CNS1 region is extended from −372 bp upstream of the isinflammatory critical for diseases.proper differentiationResearch established and immunosuppressive that FOXP3 is the transcription start site to +1746 bp of the human FOXP3 gene function of Treg cells expressionlocus. It contains in iTreg cellsTGFβ responsive element-SMAD3 (at +1544 20 isbp a region) polypeptide which growth is essential19, factor 25 forwhich peripheral regulates induction divergent of cellular FOXP3 FOXP3 acts as a transcription. regulator and switches on a complex transcriptional network that ensures the Treg phenotype processes like proliferation,. Transforming differentiation, growth and factor-β apoptosis (TGF-β) 29 and regulates the insensitivity to antigrowth signals or evasion. and functions. In one hand, FOXP321 Onacts the as other a transcriptional hand, it acts TGF-β applies a multifaceted impact on malignancy pathogenesis activator to induce the expression of CD25 (IL2-Rα) and CTLA4 (negative Co-stimulatory molecule) . of apoptosis. It induces the tumor angiogenesis, invasion, as a repressor to inhibit IL17 transcription by binding to21, RORg 22 activationand metastasis. of SMAD3 TGF-β by isphosphorylation abundantly expressed at the C-terminal in most serineof the or FOXP3 competes with AP-1 for cooperative binding with NFAT residueshuman tumors and binds to TGFβ-R1 which further triggers the FOXP3and binds promoteron the IL2 promoter is tightly to repressregulated IL2 transcriptionby a number .of studied3130, transcription factors . The functions of SMAD3 in promoting EMT is well and causeshowever, phosphorylation it has a profound of SMAD3 role which in immune further system translocate also. The human FOXP3 promoter is stretched from -6221 bp toIt isnucleus observed that tumor-secreted TGFβ acts on responder T cells region of FOXP33, 19. gene and causes permissive histone acetylation 23 The eukaryotic promoter contains several consensus SMAD3 binds to the responsive element in CNS1+
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