Skip to content
2000
Volume 32, Issue 8
  • ISSN: 0929-8665
  • E-ISSN: 1875-5305

Abstract

Introduction

is a Gram-positive bacterium that causes tuberculosis (TB). It remains viable for extended periods within host macrophages by entering a dormant state. Alpha crystallin 1 (Acr1) is a 16 kDa protein of and is reported to be highly upregulated in latent TB. Acr1 suppresses the host’s immune system by impairing the differentiation and maturation of dendritic cells and macrophages. We hypothesize that judiciously utilizes its Acr1 protein to paralyse the immune system of the host by inducing the release of IL-10 and generating an immunosuppressive environment.

Methods

We employed tools to identify highly promiscuous, IL-10-inducing and IL-6-non-inducing epitopes of . Moreover, the selected epitope was synthesized and tested for its suppressive activity and generation of Tregs.

Results

We identified the presence of a specific epitope in Acr1 (F18) that is responsible for bolstering the release of IL-10 and Tregs through tools and verified the activity by assays. In hPBMCs, the F18 epitope could suppress the proliferation of CD4 T cells stimulated with PHA and expand the pool of Tregs in a dose-dependent manner.

Discussion

The F18 epitope from ’s Acr1 protein promotes IL-10 and Treg responses without triggering pro-inflammatory IL-6, suggesting its probable immunoregulatory role. While it holds potential for treating autoimmune diseases, its impact on infection in tuberculosis should be further investigated.

Conclusion

Our findings suggest that the F18 epitope induces IL-10 production and Treg differentiation while inhibiting CD4+ T cell proliferation and IL-6 secretion, thereby promoting an immunosuppressive environment. Furthermore, this study highlights the possible role of Acr1 and its immunosuppressive epitope F18 as therapeutic agents for inducing suppressive Tregs, which may help in the management of autoimmune diseases.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ppl/10.2174/0109298665398349250728195645
2025-08-11
2026-01-31

  • From This Site

    /content/journals/ppl/10.2174/0109298665398349250728195645
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. CecilD.L. HoltG.E. ParkK.H. GadE. RastetterL. ChildsJ. HigginsD. DisisM.L. Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor activity.Cancer Res.201474102710271810.1158/0008‑5472.CAN‑13‑328624778415
     [Google Scholar]
  2. YasamutU. WisitponchaiT. LeeV.S. YamabhaiM. RangnoiK. ThongkumW. ChupraditK. TayapiwatanaC. Determination of a distinguished interferon gamma epitope recognized by monoclonal antibody relating to autoantibody associated immunodeficiency.Sci. Rep.2022121760810.1038/s41598‑022‑11774‑935534543
     [Google Scholar]
  3. SuY. RossiR. De GrootA.S. ScottD.W. Regulatory T cell epitopes (Tregitopes) in IgG induce tolerance in vivo and lack immunogenicity per se.J. Leukoc. Biol.201394237738310.1189/jlb.091244123729499
     [Google Scholar]
  4. IvanyiJ. Function and potentials of M. tuberculosis epitopes.Front. Immunol.2014510710.3389/fimmu.2014.0010724715888
     [Google Scholar]
  5. YoussefA.R. ElsonC.J. Induction of IL-10 cytokine and the suppression of T cell proliferation by specific peptides from red cell band 3 and in vivo effects of these peptides on autoimmune hemolytic anemia in NZB mice.Auto Immun. Highlights201781710.1007/s13317‑017‑0095‑428455817
     [Google Scholar]
  6. CouperK.N. BlountD.G. RileyE.M. IL-10: The master regulator of immunity to infection.J. Immunol.200818095771577710.4049/jimmunol.180.9.577118424693
     [Google Scholar]
  7. IyerS.S. ChengG. Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease.Crit. Rev. Immunol.2012321236310.1615/CritRevImmunol.v32.i1.3022428854
     [Google Scholar]
  8. HiranoT. IL-6 in inflammation, autoimmunity and cancer.Int. Immunol.202133312714810.1093/intimm/dxaa07833337480
     [Google Scholar]
  9. AliyuM. ZohoraF.T. AnkaA.U. AliK. MalekniaS. SaffariounM. AziziG. Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach.Int. Immunopharmacol.202211110913010.1016/j.intimp.2022.10913035969896
     [Google Scholar]
  10. AfzaliB. LombardiG. LechlerR.I. LordG.M. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease.Clin. Exp. Immunol.20071481324610.1111/j.1365‑2249.2007.03356.x17328715
     [Google Scholar]
  11. Dominguez-VillarM. HaflerD.A. Regulatory T cells in autoimmune disease.Nat. Immunol.201819766567310.1038/s41590‑018‑0120‑429925983
     [Google Scholar]
  12. BurkhartC. LiuG.Y. AndertonS.M. MetzlerB. WraithD.C. Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: A role for IL-10.Int. Immunol.199911101625163410.1093/intimm/11.10.162510508180
     [Google Scholar]
  13. BettelliE. Prabhu DasM. HowardE.D. WeinerH.L. SobelR.A. KuchrooV.K. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice.J. Immunol.199816173299330610.4049/jimmunol.161.7.32999759845
     [Google Scholar]
  14. GuY. YangJ. OuyangX. LiuW. LiH. YangJ. BrombergJ. ChenS.H. MayerL. UnkelessJ.C. XiongH. Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells.Eur. J. Immunol.20083871807181310.1002/eji.20083833118506885
     [Google Scholar]
  15. PasseriL. AndolfiG. BassiV. RussoF. GiacominiG. LaudisaC. MarroccoI. CesanaL. Di StefanoM. FantiL. SgaramellaP. VitaleS. ZiparoC. AuricchioR. BareraG. Di NardoG. TronconeR. GianfraniC. AnnoniA. PasseriniL. GregoriS. Tolerogenic IL-10-engineered dendritic cell-based therapy to restore antigen-specific tolerance in T cell mediated diseases.J. Autoimmun.202313810305110.1016/j.jaut.2023.10305137224733
     [Google Scholar]
  16. KeravalaA. LechmanE.R. NashJ. MiZ. RobbinsP.D. Human, viral or mutant human IL-10 expressed after local adenovirus-mediated gene transfer are equally effective in ameliorating disease pathology in a rabbit knee model of antigen-induced arthritis.Arthritis Res. Ther.200684R9110.1186/ar196016704745
     [Google Scholar]
  17. MaY. ThorntonS. DuwelL.E. BoivinG.P. GianniniE.H. LeidenJ.M. BluestoneJ.A. HirschR. Inhibition of collagen-induced arthritis in mice by viral IL-10 gene transfer.J. Immunol.199816131516152410.4049/jimmunol.161.3.15169686619
     [Google Scholar]
  18. O’NeillE.J. DayM.J. WraithD.C. IL-10 is essential for disease protection following intranasal peptide administration in the C57BL/6 model of EAE.J. Neuroimmunol.20061781-21810.1016/j.jneuroim.2006.05.03016872684
     [Google Scholar]
  19. DeselC. DorhoiA. BandermannS. GrodeL. EiseleB. KaufmannS.H.E. Recombinant BCG ΔureC hly+ induces superior protection over parental BCG by stimulating a balanced combination of type 1 and type 17 cytokine responses.J. Infect. Dis.2011204101573158410.1093/infdis/jir59221933877
     [Google Scholar]
  20. MehraA. ZahraA. ThompsonV. SirisaengtaksinN. WellsA. PortoM. KösterS. PenberthyK. KubotaY. DricotA. RoganD. VidalM. HillD.E. BeanA.J. PhilipsJ.A. Mycobacterium tuberculosis type VII secreted effector EsxH targets host ESCRT to impair trafficking.PLoS Pathog.2013910e100373410.1371/journal.ppat.100373424204276
     [Google Scholar]
  21. CambierC.J. FalkowS. RamakrishnanL. Host evasion and exploitation schemes of Mycobacterium tuberculosis.Cell201415971497150910.1016/j.cell.2014.11.02425525872
     [Google Scholar]
  22. SinghS. MauryaS.K. AqdasM. BashirH. AroraA. BhallaV. AgrewalaJ.N. Mycobacterium tuberculosis exploits MPT64 to generate myeloid-derived suppressor cells to evade the immune system.Cell. Mol. Life Sci.2022791156710.1007/s00018‑022‑04596‑536283989
     [Google Scholar]
  23. JamilB. ShahidF. HasanZ. NasirN. RazzakiT. DawoodG. HussainR. Interferonγ/IL10 ratio defines the disease severity in pulmonary and extra pulmonary tuberculosis.Tuberculosis200787427928710.1016/j.tube.2007.03.00417532265
     [Google Scholar]
  24. HerzmannC. ErnstM. EhlersS. StengerS. MaertzdorfJ. SotgiuG. LangeC. Increased frequencies of pulmonary regulatory T-cells in latent Mycobacterium tuberculosis infection.Eur. Respir. J.20124061450145710.1183/09031936.0021461122441737
     [Google Scholar]
  25. GarcíaJ.R.E. SerranoC.J. EncisoM.J.A. GasparR.O. TrujilloO.J.L. UrestiR.E.E. PortalesP.D.P. González-AmaroR. GarcíaH.M.H. Analysis of Th1, Th17 and regulatory T cells in tuberculosis case contacts.Cell. Immunol.20142891-216717310.1016/j.cellimm.2014.03.01024841855
     [Google Scholar]
  26. GreenA.M. MattilaJ.T. BigbeeC.L. BongersK.S. LinP.L. FlynnJ.L. CD4(+) regulatory T cells in a cynomolgus macaque model of Mycobacterium tuberculosis infection.J. Infect. Dis.2010202453354110.1086/65489620617900
     [Google Scholar]
  27. StringariL.L. CovreL.P. da SilvaF.D.C. de OliveiraV.L. CampanaM.C. HadadD.J. PalaciM. SalgameP. DietzeR. GomesD.C.O. Ribeiro-RodriguesR. Increase of CD4+CD25highFoxP3+ cells impairs in vitro human microbicidal activity against Mycobacterium tuberculosis during latent and acute pulmonary tuberculosis.PLoS Negl. Trop. Dis.2021157e000960510.1371/journal.pntd.000960534324509
     [Google Scholar]
  28. BabuS. BhatS.Q. KumarN.P. KumaraswamiV. NutmanT.B. Regulatory T cells modulate Th17 responses in patients with positive tuberculin skin test results.J. Infect. Dis.20102011203110.1086/64873519929695
     [Google Scholar]
  29. KennawayC.K. BeneschJ.L.P. GohlkeU. WangL. RobinsonC.V. OrlovaE.V. SaibiH.R. KeepN.H. Dodecameric structure of the small heat shock protein Acr1 from Mycobacterium tuberculosis.J. Biol. Chem.200528039334193342510.1074/jbc.M50426320016046399
     [Google Scholar]
  30. HealyE.F. GoeringL.M. HauserC.R. KingP.J. An immunomodulatory role for the Mycobacterium tuberculosis Acr protein in the formation of the tuberculous granuloma.FEBS Lett.2021595228429310.1002/1873‑3468.1399833185291
     [Google Scholar]
  31. SiddiquiK.F. AmirM. GurramR.K. KhanN. AroraA. RajagopalK. AgrewalaJ.N. Latency-associated protein Acr1 impairs dendritic cell maturation and functionality: A possible mechanism of immune evasion by Mycobacterium tuberculosis.J. Infect. Dis.201420991436144510.1093/infdis/jit59524218502
     [Google Scholar]
  32. MubinN. PahariS. OwaisM. ZubairS. Mycobacterium tuberculosis host cell interaction: Role of latency associated protein Acr-1 in differential modulation of macrophages.PLoS One20181311e020645910.1371/journal.pone.020645930395609
     [Google Scholar]
  33. AmirM. AqdasM. NadeemS. SiddiquiK.F. KhanN. SheikhJ.A. AgrewalaJ.N. Diametric role of the latency-associated protein Acr1 of Mycobacterium tuberculosis in modulating the functionality of pre- and post-maturational stages of dendritic cells.Front. Immunol.2017862410.3389/fimmu.2017.0062428611779
     [Google Scholar]
  34. YuanY. CraneD.D. SimpsonR.M. ZhuY. HickeyM.J. ShermanD.R. Barry IIIC.E. The 16-kDa α-crystallin (Acr) protein of Mycobacterium tuberculosis is required for growth in macrophages.Proc. Natl. Acad. Sci. USA199895169578958310.1073/pnas.95.16.95789689123
     [Google Scholar]
  35. JurcevicS. HillsA. PasvolG. DavidsonR.N. IvanyiJ. WilkinsonR.J. T cell responses to a mixture of Mycobacterium tuberculosis peptides with complementary HLA-DR binding profiles.Clin. Exp. Immunol.2003105341642110.1046/j.1365‑2249.1996.d01‑791.x8809128
     [Google Scholar]
  36. CaccamoN. BareraA. Di SanoC. MeravigliaS. IvanyiJ. HudeczF. BoszeS. DieliF. SalernoA. Cytokine profile, HLA restriction and TCR sequence analysis of human CD4+ T clones specific for an immunodominant epitope of Mycobacterium tuberculosis 16-kDa protein.Clin. Exp. Immunol.2003133226026610.1046/j.1365‑2249.2003.02201.x12869033
     [Google Scholar]
  37. AgrewalaJ.N. WilkinsonR.J. Influence of HLA-DR on the phenotype of CD4+ T lymphocytes specific for an epitope of the 16-kDa α-crystallin antigen of Mycobacterium tuberculosis.Eur. J. Immunol.19992961753176110.1002/(SICI)1521‑4141(199906)29:06<1753::AID‑IMMU1753>3.0.CO;2‑B10382737
     [Google Scholar]
  38. AgrewalaJ.N. WilkinsonR.J. Differential regulation of Th1 and Th2 cells by p91–110 and p21–40 peptides of the 16-kD α-crystallin antigen of Mycobacterium tuberculosis .Clin. Exp. Immunol.2001114339239710.1046/j.1365‑2249.1998.00724.x9844048
     [Google Scholar]
  39. ShamsH. KlucarP. WeisS.E. LalvaniA. MoonanP.K. SafiH. WizelB. EwerK. NepomG.T. LewinsohnD.M. AndersenP. BarnesP.F. Characterization of a Mycobacterium tuberculosis peptide that is recognized by human CD4+ and CD8+ T cells in the context of multiple HLA alleles.J. Immunol.200417331966197710.4049/jimmunol.173.3.196615265931
     [Google Scholar]
  40. ValleM.T. MegiovanniA.M. MerloA. Li PiraG. BottoneL. AngeliniG. BracciL. LozziL. HuygenK. MancaF. Epitope focus, clonal composition and Th1 phenotype of the human CD4 response to the secretory mycobacterial antigen Ag85.Clin. Exp. Immunol.2001123222623210.1046/j.1365‑2249.2001.01450.x11207652
     [Google Scholar]
  41. NagpalG. UsmaniS.S. DhandaS.K. KaurH. SinghS. SharmaM. RaghavaG.P.S. Computer-aided designing of immunosuppressive peptides based on IL-10 inducing potential.Sci. Rep.2017714285110.1038/srep4285128211521
     [Google Scholar]
  42. DhallA. PatiyalS. SharmaN. UsmaniS.S. RaghavaG.P.S. Computer-aided prediction and design of IL-6 inducing peptides: IL-6 plays a crucial role in COVID-19.Brief. Bioinform.202122293694510.1093/bib/bbaa25933034338
     [Google Scholar]
  43. VitaR. MahajanS. OvertonJ.A. DhandaS.K. MartiniS. CantrellJ.R. WheelerD.K. SetteA. PetersB. The immune epitope database (IEDB): 2018 update.Nucleic Acids Res.201947D1D339D34310.1093/nar/gky100630357391
     [Google Scholar]
  44. RapinN. LundO. CastiglioneF. Immune system simulation online.Bioinformatics201127142013201410.1093/bioinformatics/btr33521685045
     [Google Scholar]
  45. LamiableA. ThévenetP. ReyJ. VavrusaM. DerreumauxP. TufféryP. PEP-FOLD3: Faster de novo structure prediction for linear peptides in solution and in complex.Nucleic Acids Res.201644W1W449W45410.1093/nar/gkw32927131374
     [Google Scholar]
  46. KozakovD. HallD.R. XiaB. PorterK.A. PadhornyD. YuehC. BeglovD. VajdaS. The ClusPro web server for protein–protein docking.Nat. Protoc.201712225527810.1038/nprot.2016.16928079879
     [Google Scholar]
  47. BehrendtR. WhiteP. OfferJ. Advances in Fmoc solid-phase peptide synthesis.J. Pept. Sci.201622142710.1002/psc.283626785684
     [Google Scholar]
/content/journals/ppl/10.2174/0109298665398349250728195645
Loading
F18 Promiscuous Epitope of Acr1 Protein of Mycobacterium tuberculosis Induces the Secretion of IL-10 and Tregs but Not IL-6
PPL 32, 610 (2025); https://doi.org/10.2174/0109298665398349250728195645
/content/journals/ppl/10.2174/0109298665398349250728195645
/content/journals/ppl/10.2174/0109298665398349250728195645
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

file format download Download

  • Article Type:     Rapid Communication
Keyword(s): Acr1; autoimmunity; IL-10; immunosuppressive epitopes; Mycobacterium tuberculosis; Tregs

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test