Advances in Cancer Immunotherapy and Stem Cell Research

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DOI :10.26650/B/LS17LS30.2025.038.007   IUP :10.26650/B/LS17LS30.2025.038.007    Full Text (PDF)

The Role of CD8+CXCR5+ Follicular Cytotoxic T cell and Their Subsets in B Cell Responses and Diseases

Fatih Akboğa, Fehmi Hindilerden, Günnur Deniz, Metin Yusuf Gelmez

CXCR5 expressing CD8+ T cells called follicular cytotoxic CD8+ T (T𝐹𝐶) cells differ phenotypically and transcriptionally from other CD8+ T cells. T𝐹𝐶 migrates to B cell follicles and eliminates infected or malignant B and follicular helper T (T𝐹𝐻) cells secreting perforin and granzyme. Recent studies showed that there is a subset of T𝐹𝐶 that support antibody responses in B cells by expressing CD40L or ICOS. The studies showed that there is a correlation between the frequency and cytolytic function of T𝐹𝐶 cells and the viral load in chronic infections. T𝐹𝐶 have been reported to infiltrate the tumor and nearby lymph nodes in colorectal cancer patients, and levels of TNF-𝛼, IFN-𝛾, granzyme-B, and T𝐹𝐶 frequency are positively correlated with disease prognosis. The cytotoxic effect of T𝐹𝐶 in CLL has been analyzed, but the CD40L-mediated stimulatory effect of T𝐹𝐶 has not been examined yet. Based on the literature, whether T𝐹𝐶 cells and subsets in CLL patients stimulate malignant B cells and increase proliferation, like the T𝐹𝐻 phenotype, or whether they affect malignant B cell lysis via perforin and granzyme were investigated. It provides information about the functional properties, similarities, and differences of ICOS+ T𝐹𝐶, CD40L+ T𝐹𝐶, and ICOS−CD40L−(Double Negative-DN) T𝐹𝐶 subsets defined. In addition, it has been shown that CD40L+ T𝐹𝐶 have the effect of enhancing IgG responses of B cells. However, ICOS+ T𝐹𝐶 express high amount of perforin and granzyme. Further studies are needed to understand the role of T𝐹𝐶 subset in the pathogenesis of diseases such as B cell malignancy.


Keywords: Chronic lymphocytic leukemia, CLL, follicular cytotoxic CD8+ T cell, T𝐹𝐶, follicular helper CD4+ T cell, T𝐹𝐻, cytotoxicity

References

  • 1. Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol. 2012;12(11):749-61. google scholar
  • 2. Castelli C, Rivoltini L, Andreola G, Carrabba M, Renkvist N, Parmiani G. T-cell recognition of melanoma-associated antigens. J Cell Physiol. 2000;182(3):323-31. google scholar
  • 3. Xin A, Masson F, Liao Y, Preston S, Guan T, Gloury R, et al. A molecular threshold for effector CD8(+) T cell differentiation controlled by transcription factors Blimp-1 and T-bet. Nat Immunol. 2016;17(4):422-32. google scholar
  • 4. Basu R, Whitlock BM, Husson J, Le Floc’h A, Jin W, Oyler-Yaniv A, et al. Cytotoxic T cells use mechanical force to potentiate target cell killing. Cell. 2016;165(1):100-10. google scholar
  • 5. Gordy C, He YW. Endocytosis by target cells: an essential means for perforin- and granzyme-mediated killing. Cell Mol Immunol. 2012;9(1):5-6. google scholar
  • 6. Gerritsen B, Pandit A. The memory of a killer T cell: models of CD8(+) T cell differentiation. İmmunol Cell Biol. 2016;94(3):236-41. google scholar
  • 7. Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. İmmunity. 2011;35(2):161-8. google scholar
  • 8. Vacca P, Munari E, Tumino N, Moretta F, Pietra G, Vitale M, et al. Human natural killer cells and other innate lymphoid cells in cancer: friends or foes? İmmunol Lett. 2018;201:14-9. google scholar
  • 9. Brazin KN, Mallis RJ, Das DK, Feng Y, Hwang W, Wang JH, et al. Structural features of the alphabetaTCR mechanotransduction apparatus that promote pMHC discrimination. Front İmmunol. 2015;6:441. google scholar
  • 10. Samji T, Khanna KM. Understanding memory CD8(+) T cells. İmmunol Lett. 2017;185:32-9. google scholar
  • 11. Mandl JN, Liou R, Klauschen F, Vrisekoop N, Monteiro JP, Yates AJ, et al. Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naive CD4+ and CD8+ T cells. Proc Natl Acad Sci USA. 2012;109(44):18036-41. google scholar
  • 12. Von Andrian UH, Mempel TR. Homing and cellular traffic in lymph nodes. Nat Rev İmmunol. 2003;3(11):867-78. google scholar
  • 13. Osinska İ, Popko K, Demkow U. Perforin: an important player in immune response. Cent Eur J İmmunol. 2014;39(1):109-15. google scholar
  • 14. Nagata S. Fas-mediated apoptosis. Adv Exp Med Biol. 1996;406:119-24. google scholar
  • 15. El-Guindy DM, Helal DS, Sabry NM, Abo El-Nasr M. Programmed cell death ligand-1 (PD-L1) expression combined with CD8 tumor infiltrating lymphocytes density in non-small cell lung cancer patients. J Egypt Natl Canc İnst. 2018;30(4):125-31. google scholar
  • 16. Pawlowska A, Suszczyk D, Okla K, Barczynski B, Kotarski J, Wertel İ. İmmunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment. Clin Exp İmmunol. 2019;195(3):334-44. google scholar
  • 17. Sun H, Sun C, Xiao W, Sun R. Tissue-resident lymphocytes: from adaptive to innate immunity. Cell Mol İmmunol. 2019;16(3):205-15. google scholar
  • 18. Raskov H, Orhan A, Christensen JP, Gogenur İ. Cytotoxic CD8(+) T cells in cancer and cancer immunotherapy. Br J Cancer. 2021;124(2):359-67. google scholar
  • 19. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med. 1998;188(12):2205-13. google scholar
  • 20. McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2019;37:457-95. google scholar
  • 21. Reina-Campos M, Scharping NE, Goldrath AW. CD8(+) T cell metabolism in infection and cancer. Nat Rev Immunol. 2021;21(11):718-38. google scholar
  • 22. He R, Hou S, Liu C, Zhang A, Bai Q, Han M, et al. Follicular CXCR5- expressing CD8(+) T cells curtail chronic viral infection. Nature. 2016;537(7620):412-28. google scholar
  • 23. Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M, Moser B. B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J Exp Med. 1998;187(4):655-60. google scholar
  • 24. Ma QY, Chen J, Zhao J. Follicular cytotoxic CD8 T cells present high cytokine expression, and are more susceptible to Breg-mediated suppression in non-small cell lung cancer. Immunol Res. 2020;68(1):54-62. google scholar
  • 25. Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29:621-63. google scholar
  • 26. Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34(1):108-21. google scholar
  • 27. Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014;41(4):529-42. google scholar
  • 28. Quigley MF, Gonzalez VD, Granath A, Andersson J, Sandberg JK. CXCR5+ CCR7-CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles. Eur J Immunol. 2007;37(12):3352-62. google scholar
  • 29. Yu D, Ye L. A Portrait of CXCR5(+) Follicular cytotoxic CD8(+) T cells. Trends Immunol. 2018;39(12):965-79. google scholar
  • 30. Ferrando-Martinez S, Moysi E, Pegu A, Andrews S, Nganou Makamdop K, Ambrozak D, et al. Accumulation of follicular CD8+ T cells in pathogenic SIV infection. J Clin Invest. 2018;128(5):2089-103. google scholar
  • 31. E J, Yan F, Kang Z, Zhu L, Xing J, Yu E. CD8(+)CXCR5(+) T cells in tumor-draining lymph nodes are highly activated and predict better prognosis in colorectal cancer. Hum İmmunol. 2018;79(6):446-52. google scholar
  • 32. İm SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537(7620):417-21. google scholar
  • 33. Leong YA, Chen Y, Ong HS, Wu D, Man K, Deleage C, et al. CXCR5(+) follicular cytotoxic T cells control viral infection in B cell follicles. Nat İmmunol. 2016;17(10):1187-96. google scholar
  • 34. Mylvaganam GH, Rios D, Abdelaal HM, İyer S, Tharp G, Mavigner M, et al. Dynamics of SİV-specific CXCR5+ CD8 T cells during chronic SİV infection. Proc Natl Acad Sci USA. 2017;114(8):1976-81. google scholar
  • 35. Bai M, Zheng Y, Liu H, SuB, Zhan Y, HeH. CXCR5(+) CD8(+) T cells potently infiltrate pancreatic tumors and present high functionality. Exp Cell Res. 2017;361(1):39-45. google scholar
  • 36. Tang J, Zha J, Guo X, Shi P, Xu B. CXCR5(+)CD8(+) T cells present elevated capacity in mediating cytotoxicity toward autologous tumor cells through interleukin 10 in diffuse large B-cell lymphoma. İnt İmmunopharmacol. 2017;50:146-51. google scholar
  • 37. Petrovas C, Ferrando-Martinez S, Gerner MY, Casazza JP, Pegu A, Deleage C, et al. Follicular CD8 T cells accumulate in HİV infection and can kill infected cells in vitro via bispecific antibodies. Sci Transl Med. 2017;9(373):eaag2285. google scholar
  • 38. Jiang H, Li L, Han J, Sun Z, Rong Y, Jin Y. CXCR5(+) CD8(+) T cells İndirectly offer B cell help and are inversely correlated with viral load in chronic hepatitis B infection. DNA Cell Biol. 2017;36(4):321-7. google scholar
  • 39. Shen J, Luo X, Wu Q, Huang J, Xiao G, Wang L, et al. A subset of CXCR5(+)CD8(+) T Cells in the germinal centers from human tonsils and lymph nodes help B cells produce immunoglobulins. Front İmmunol. 2018;9:2287. google scholar
  • 40. Kim HJ, Verbinnen B, Tang X, Lu L, Cantor H. İnhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature. 2010;467(7313):328-32. google scholar
  • 41. Miles B, Miller SM, Folkvord JM, Levy DN, Rakasz EG, Skinner PJ, et al. Follicular regulatory CD8 T cells impair the germinal center response in SİV and ex vivo HİV infection. PLoS Pathog. 2016;12(10):e1005924. google scholar
  • 42. Brummelman J, Mazza EMC, Alvisi G, Colombo FS, Grilli A, Mikulak J, et al. High-dimensional single cell analysis identifies stem-like cytotoxic CD8(+) T cells infiltrating human tumors. J Exp Med. 2018;215(10):2520-35. google scholar
  • 43. Connick E, Folkvord JM, Lind KT, Rakasz EG, Miles B, Wilson NA, et al. Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL. J Immunol. 2014;193(11):5613-25. google scholar
  • 44. Rahman MA, McKinnon KM, Karpova TS, Ball DA, Venzon DJ, Fan W, et al. Associations of simian immunodeficiency virus (SIV)-Specific follicular CD8(+) T cells with other follicular T cells suggest complex contributions to SIV viremia control. J Immunol. 2018;200(8):2714-26. google scholar
  • 45. Lindqvist M, van Lunzen J, Soghoian DZ, Kuhl BD, Ranasinghe S, Kranias G, et al. Expansion of HIV-specific T follicular helper cells in chronic HIV infection. J Clin Invest. 2012;122(9):3271-80. google scholar
  • 46. Pissani F, Streeck H. Emerging concepts on T follicular helper cell dynamics in HIV infection. Trends Immunol. 2014;35(6):278-86. google scholar
  • 47. Zhou Y, Guo L, Sun H, Xu J, Ba T. CXCR5(+) CD8 T cells displayed higher activation potential despite high PD-1 expression, in tumor-involved lymph nodes from patients with thyroid cancer. Int Immunopharmacol. 2018;62:114-9. google scholar
  • 48. Hofland T, Martens AWJ, van Bruggen JAC, de Boer R, Schetters S, Remmerswaal EBM, et al. Human CXCR5(+) PD-1(+) CD8 T cells in healthy individuals and patients with hematologic malignancies. Eur J Immunol. 2021;51(3):703-13. google scholar
  • 49. Gelmez MY, Oktelik FB, Cinar S, Ozbalak M, Ozluk O, Aktan M, et al. High expression of OX-40, ICOS, and low expression PD-L1 of follicular helper and follicular cytotoxic T cells in chronic lymphocytic leukemia. J Hematop. 2022;15(3):117-29. google scholar
  • 50. ChuF,LiHS,LiuX,CaoJ,MaW,MaY,etal. CXCR5(+)CD8(+) T cells are a distinct functional subset with an antitumor activity. Leukemia. 2019;33(11):2640-53. google scholar
  • 51. Le KS, Ame-Thomas P, Tarte K, Gondois-Rey F, Granjeaud S, Orlanducci F, et al. CXCR5 and ICOS expression identifies a CD8 T-cell subset with TFH features in Hodgkin lymphomas. Blood Adv. 2018;2(15):1889-900. google scholar


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