Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice

European Journal of Immunology

Volumn 46, Issue 5, 2016, Pages 1152-1161

  Wu, Hao ^a   Chen, Yuxin ^b   Liu, Hong ^a   Xu, Lin Lin ^a   Teuscher, Paula ^a   Wang, Shixia ^b   Lu, Shan ^b   Dent, Alexander L ^a  

^a INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

Author keywords

Antibody; Bcl6; Follicular T cells; Germinal Center Response; Regulatory T cells

Indexed keywords

GAMMA INTERFERON; IMMUNOGLOBULIN A; IMMUNOGLOBULIN G; IMMUNOGLOBULIN G ANTIBODY; INTERLEUKIN 10; INTERLEUKIN 21; PROTEIN BCL 6; BCL6 PROTEIN, MOUSE; CYTOKINE; DNA; FORKHEAD TRANSCRIPTION FACTOR; FOXP3 PROTEIN, MOUSE; GLYCOPROTEIN GP 120; HUMAN IMMUNODEFICIENCY VIRUS ANTIBODY; IL10 PROTEIN, MOUSE; INTERLEUKIN DERIVATIVE;

ANIMAL EXPERIMENT; ANTIBODY RESPONSE; ANTIBODY TITER; ARTICLE; CELL LOSS; CONTROLLED STUDY; CYTOKINE PRODUCTION; GENE DELETION; HELPER CELL; MOUSE; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; ANIMAL; ANTIBODY AFFINITY; AUTOIMMUNITY; BIOSYNTHESIS; DEFICIENCY; GENETICS; GERMINAL CENTER; IMMUNOLOGY; METABOLISM; PHYSIOLOGY; SYSTEMIC LUPUS ERYTHEMATOSUS; VACCINATION;

ANIMALS; ANTIBODY AFFINITY; AUTOIMMUNITY; CYTOKINES; DNA; FORKHEAD TRANSCRIPTION FACTORS; GERMINAL CENTER; HIV ANTIBODIES; HIV ENVELOPE PROTEIN GP120; IMMUNOGLOBULIN A; IMMUNOGLOBULIN G; INTERFERON-GAMMA; INTERLEUKIN-10; INTERLEUKINS; LUPUS ERYTHEMATOSUS, SYSTEMIC; MICE; PROTO-ONCOGENE PROTEINS C-BCL-6; T-LYMPHOCYTES, HELPER-INDUCER; T-LYMPHOCYTES, REGULATORY; VACCINATION;

EID: 84960391287     PISSN: 00142980     EISSN: 15214141     Source Type: Journal    
DOI: 10.1002/eji.201546094     Document Type: Article

References (46)

1. Fazilleau, N., Mark, L., McHeyzer-Williams, L. J. and McHeyzer-Williams, M. G., Follicular helper T cells: lineage and location. Immunity 2009. 30: 324-335.
2. Crotty, S., Johnston, R. J. and Schoenberger, S. P., Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat. Immunol. 2010. 11: 114-120.
3. McHeyzer-Williams, L. J., Pelletier, N., Mark, L., Fazilleau, N. and McHeyzer-Williams, M. G., Follicular helper T cells as cognate regulators of B cell immunity. Curr. Opin. Immunol. 2009. 21: 266-273.
4. Breitfeld, D., Ohl, L., Kremmer, E., Ellwart, J., Sallusto, F., Lipp, M. and Forster, R., Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 2000. 192: 1545-1552.
5. Schaerli, P., Willimann, K., Lang, A. B., Lipp, M., Loetscher, P. and Moser, B., CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 2000. 192: 1553-1562.
6. Vinuesa, C. G., Cook, M. C., Angelucci, C., Athanasopoulos, V., Rui, L., Hill, K. M., Yu, D. et al., A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 2005. 435: 452-458.
7. Linterman, M. A., Rigby, R. J., Wong, R. K., Yu, D., Brink, R., Cannons, J. L., Schwartzberg, P. L. et al., Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 2009. 206: 561-576.
8. Odegard, J. M., Marks, B. R., DiPlacido, L. D., Poholek, A. C., Kono, D. H., Dong, C., Flavell, R. A. et al., ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J. Exp. Med. 2008. 205: 2873-2886.
9. Chung, Y., Tanaka, S., Chu, F., Nurieva, R. I., Martinez, G. J., Rawal, S., Wang, Y. H. et al., Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 2011. 17: 983-988.
10. + follicular regulatory T cells control the germinal center response. Nat. Med. 2011. 17: 975-982.
11. + follicular regulatory T cells. J. Immunol. 2011. 187: 4553-4560.
12. Sage, P. T., Alvarez, D., Godec, J., von Andrian, U. H. and Sharpe, A. H., Circulating T follicular regulatory and helper cells have memory-like properties. J. Clin. Invest. 2014. 124: 5191-5204.
13. Sage, P. T., Francisco, L. M., Carman, C. V. and Sharpe, A. H., The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat. Immunol. 2013. 14: 152-161.
14. Vaeth, M., Muller, G., Stauss, D., Dietz, L., Klein-Hessling, S., Serfling, E., Lipp, M. et al., Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression. J. Exp. Med. 2014. 211: 545-561.
15. Sage, P. T., Tan, C. L., Freeman, G. J., Haigis, M. and Sharpe, A. H., Defective TFH cell function and increased TFR cells contribute to defective antibody production in aging. Cell Rep. 2015. 12: 163-171.
16. + regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat. Commun. 2014. 5: 3495.
17. Sage, P. T., Paterson, A. M., Lovitch, S. B. and Sharpe, A. H., The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 2014. 41: 1026-1039.
18. Crotty, S., Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 2011. 29: 621-663.
19. Nurieva, R. I., Podd, A., Chen, Y., Alekseev, A. M., Yu, M., Qi, X., Huang, H. et al., STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J. Biol. Chem. 2012. 287: 11234-11239.
20. Johnston, R. J., Choi, Y. S., Diamond, J. A., Yang, J. A. and Crotty, S., STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 2012. 209: 243-250.
21. Ballesteros-Tato, A., Leon, B., Graf, B. A., Moquin, A., Adams, P. S., Lund, F. E. and Randall, T. D., Interleukin-2 inhibits germinal center formation by limiting t follicular helper cell differentiation. Immunity 2012. 36: 847-856.
22. Locci, M., Havenar-Daughton, C., Landais, E., Wu, J., Kroenke, M. A., Arlehamn, C. L., Su, L. F. et al., Human circulating PD-1(+)1CXCR3(-)CXCR5(+) memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses. Immunity 2013. 39: 758-69.
23. Seth, S., Ravens, I., Kremmer, E., Maier, M. K., Hadis, U., Hardtke, S., Forster, R. et al., Abundance of follicular helper T cells in Peyer's patches is modulated by CD155. Eur. J. Immunol. 2009. 39: 3160-3170.
24. Joller, N., Lozano, E., Burkett, P. R., Patel, B., Xiao, S., Zhu, C., Xia, J. et al., Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 2014. 40: 569-581.
25. Hollister, K., Kusam, S., Wu, H., Clegg, N., Mondal, A., Sawant, D. V. and Dent, A. L., Insights into the role of Bcl6 in follicular Th cells using a new conditional mutant mouse model. J. Immunol. 2013. 191: 3705-3711.
26. Sawant, D. V., Wu, H., Yao, W., Sehra, S., Kaplan, M. H. and Dent, A. L., The transcriptional repressor Bcl6 controls the stability of regulatory T cells by intrinsic and extrinsic pathways. Immunology 2015. 145: 11-23.
27. Dent, A. L., Shaffer, A. L., Yu, X., Allman, D. and Staudt, L. M., Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 1997. 276: 589-592.
28. Sawant, D. V., Sehra, S., Nguyen, E. T., Jadhav, R., Englert, K., Shinnakasu, R., Hangoc, G. et al., Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing Gata3 function. J. Immunol. 2012. 189: 4759-4769.
29. Hollister, K., Chen, Y., Wang, S., Wu, H., Mondal, A., Clegg, N., Lu, S. et al., The role of follicular helper T cells and the germinal center in HIV-1 gp120 DNA prime and gp120 protein boost vaccination. Hum. Vaccin. Immunother. 2014. 10: 1985-1992.
30. Wang, S., Arthos, J., Lawrence, J. M., Van Ryk, D., Mboudjeka, I., Shen, S., Chou, T. H. et al., Enhanced immunogenicity of gp120 protein when combined with recombinant DNA priming to generate antibodies that neutralize the JR-FL primary isolate of human immunodeficiency virus type 1. J. Virol. 2005. 79: 7933-7937.
31. +CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J. Immunol. 2007. 178: 2579-2588.
32. Bonelli, M., Smolen, J. S. and Scheinecker, C., Treg and lupus. Ann. Rheum. Dis. 2010. 69 (Suppl 1), i65-i66.
33. Satoh, M. and Reeves, W. H., Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. J. Exp. Med. 1994. 180: 2341-2346.
34. Richards, H. B., Satoh, M., Shaw, M., Libert, C., Poli, V. and Reeves, W. H., Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus. J. Exp. Med. 1998. 188: 985-990.
35. Wu, H., Xu, L. L., Teuscher, P., Liu, H., Kaplan, M. H. and Dent, A. L., An inhibitory role for the transcription factor stat3 in controlling IL-4 and Bcl6 expression in follicular helper t cells. J. Immunol. 2015. 195: 2080-2089.
36. + regulatory T cell survival. Biol. Direct 2008. 3: 6.
37. Wang, J., Wicker, L. S. and Santamaria, P., IL-2 and its high-affinity receptor: genetic control of immunoregulation and autoimmunity. Semin. Immunol. 2009. 21: 363-371.
38. Zotos, D. and Tarlinton, D. M., Determining germinal centre B cell fate. Trends Immunol. 2012. 33: 281-288.
39. Ozaki, K., Spolski, R., Feng, C. G., Qi, C. F., Cheng, J., Sher, A., Morse, H. C. 3rd. et al., A critical role for IL-21 in regulating immunoglobulin production. Science 2002. 298: 1630-1634.
40. Grammer, A. C., Slota, R., Fischer, R., Gur, H., Girschick, H., Yarboro, C., Illei, G. G. et al., Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. J. Clin. Invest 2003. 112: 1506-1520.
41. Perry, D., Sang, A., Yin, Y., Zheng, Y.-Y. and Morel, L., Murine models of systemic lupus erythematosus. J. Biomed. Biotechnol. 2011. doi:10.1155/2011/271694.
42. Lee, S. K., Silva, D. G., Martin, J. L., Pratama, A., Hu, X., Chang, P. P., Walters, G. et al., Interferon-gamma excess leads to pathogenic accumulation of follicular helper T cells and germinal centers. Immunity 2012. 37: 880-892.
43. Sweet, R. A., Lee, S. K. and Vinuesa, C. G., Developing connections amongst key cytokines and dysregulated germinal centers in autoimmunity. Curr. Opin. Immunol. 2012. 24: 658-664.
44. Miltenburg, A. M., Roos, A., Slegtenhorst, L., Daha, M. R. and Breedveld, F. C., IgA anti-dsDNA antibodies in systemic lupus erythematosus: occurrence, incidence and association with clinical and laboratory variables of disease activity. J. Rheumatol. 1993. 20: 53-58.
45. Villalta, D., Bizzaro, N., Bassi, N., Zen, M., Gatto, M., Ghirardello, A., Iaccarino, L. et al., Anti-dsDNA antibody isotypes in systemic lupus erythematosus: IgA in addition to IgG anti-dsDNA help to identify glomerulonephritis and active disease. PLoS One 2013. 8: e71458.
46. Rubtsov, Y. P., Rasmussen, J. P., Chi, E. Y., Fontenot, J., Castelli, L., Ye, X., Treuting, P. et al., Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 2008. 28: 546-558.