Abstract
Follicular helper T cells (Tfh) represent a distinct subset of CD4+ T cells specialized in providing help to B lymphocytes. Studies have indicated that Tfh in circulating blood can act as a prognostic marker for diseases. In the current study, we investigated the percentages of circulating Tfh (CTfh) in Crohn’s disease (CD) and CD-associated colorectal cancer (CRC). CTfh and it subtypes were determined by measuring CD3, CD4, CXCR5, CXCR3, and CCR6 using flow cytometry in 32 healthy controls and 78 CD patients, which included 16 CD-associated CRC. Data showed that proportion of CTfh in CD4+ T cells was significantly increased in CD patients (9.8 %) than in controls (5.1 %) (p < 0.01). Further analysis revealed that the upregulation of CTfh was contributed by CTfh-Th1 subtype and CTfh-Th17 subtype. Investigating the behavior of the patients demonstrated that prevalence of CTfh was significantly elevated in penetrating CD (20.9 %) than inflammatory CD (8.2 %) or stricturing CD (7.5 %). In addition, we analyzed CTfh in CD-associated CRC, and identified that patients with CRC had 1.59-fold higher percentage of CTfh than patients without CRC (p < 0.01). Furthermore, the distribution of CTfh subsets was significantly altered in patients with the cancer. This study suggests the involvement of CTfh in CD and CD-associated CRC, in which the effect of CTfh is partially different between these two diseases.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, et al. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol. 2000;165:6037–46.
Li X, Shi W, Yu G, Lin L, Yang B, et al. Interleukin-4–590T/C polymorphism influences the susceptibility to nonsmall cell lung cancer. DNA Cell Biol. 2012;31:797–800.
Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29:621–63.
Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009;325:1006–10.
Ma CS, Suryani S, Avery DT, Chan A, Nanan R, et al. Early commitment of naive human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12. Immunol Cell Biol. 2009;87:590–600.
Akiba H, Takeda K, Kojima Y, Usui Y, Harada N, et al. The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J Immunol. 2005;175:2340–8.
Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho IC, et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol. 2009;10:167–75.
Rasheed AU, Rahn HP, Sallusto F, Lipp M, Muller G. Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression. Eur J Immunol. 2006;36:1892–903.
Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. Blood. 2007;110:2537–44.
Bossaller L, Burger J, Draeger R, Grimbacher B, Knoth R, et al. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J Immunol. 2006;177:4927–32.
Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum. 2010;62:234–44.
Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, 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;34:108–21.
Ame-Thomas P, Maby-El Hajjami H, Monvoisin C, Jean R, Monnier D, et al. Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis. Blood. 2007;109:693–702.
Clear AJ, Lee AM, Calaminici M, Ramsay AG, Morris KJ, et al. Increased angiogenic sprouting in poor prognosis FL is associated with elevated numbers of CD163+ macrophages within the immediate sprouting microenvironment. Blood. 2010;115:5053–6.
Havenith SH, Remmerswaal EB, Idu MM, van Donselaar-van der Pant KA, van der Bom N, et al. (2013) CXCR5+CD4+ follicular helper T cells accumulate in resting human lymph nodes and have superior B cell helper activity. Int Immunol
He J, Tsai LM, Leong YA, Hu X, Ma CS, et al. Circulating precursor CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity. 2013;39:770–81.
Qi H, Chen X, Chu C, Lu P, Xu H, et al. Follicular T-helper cells: controlled localization and cellular interactions. Immunol Cell Biol. 2014;92:28–33.
Xiao F, Zhang HY, Liu YJ, Zhao D, Shan YX, et al. Higher frequency of peripheral blood interleukin 21 positive follicular helper T cells in patients with ankylosing spondylitis. J Rheumatol. 2013;40:2029–37.
Faghih Z, Erfani N, Haghshenas MR, Safaei A, Talei AR, et al. Immune profiles of CD4+ lymphocyte subsets in breast cancer tumor draining lymph nodes. Immunol Lett. 2013;158:57–65.
Zhao Y, Lutalo PM, Thomas JE, Sangle S, Choong LM, et al. Circulating T follicular helper cell and regulatory T cell frequencies are influenced by B cell depletion in patients with granulomatosis with polyangiitis. Rheumatology (Oxford). 2013;53:621–30.
Cha Z, Zang Y, Guo H, Rechlic JR, Olasnova LM, et al. Association of peripheral CD4+ CXCR5+ T cells with chronic lymphocytic leukemia. Tumour Biol. 2013;34:3579–85.
Conflicts of interest
None
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, Z., Wang, Z., Diao, Y. et al. Circulating follicular helper T cells in Crohn’s disease (CD) and CD-associated colorectal cancer. Tumor Biol. 35, 9355–9359 (2014). https://doi.org/10.1007/s13277-014-2208-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-014-2208-2