Cd1d regulates B cell development but not B cell accumulation and IL10 production in mice with pathologic CD5 + B cell expansion

BMC Immunology

Patrick C. Swanson¹  Greg A. Perry¹  Mary E. Rothermund¹  Vincent K. Nganga¹  Victoria L. Palmer¹ 

[1] Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha 68178, NE, USA

关键词: TCL1;    CD5;    Natural killer T cell;    B10 B cell;    CLL;    CD1d;   

Others  :  1233004
DOI  :  10.1186/s12865-015-0130-z

 received in 2015-08-11, accepted in 2015-10-20,  发布年份 2015

【 摘 要 】

Background

CD1d is a widely expressed lipid antigen presenting molecule required for CD1d-restricted invariant natural killer T (iNKT) cell development. Elevated CD1d expression is detected in CD5 ⁺IL10-producing B cells, called B10 B cells, and is correlated with poorer prognosis in chronic lymphocytic leukemia (CLL), a CD5 ⁺B cell malignancy with B10-like functional properties. Whether CD1d expression regulates CD5 ⁺B cell accumulation, IL10 competence, and antibody production in naïve mice with pathologic CD5 ⁺B cell expansion remains untested.

Results

Using three different transgenic mouse models of benign or leukemic CD5 ⁺B cell expansion, we found that CD1d was differentially expressed on CD5 ⁺B cells between the three models, but loss of CD1d expression had no effect on CD5 ⁺B cell abundance or inducible IL10 expression in any of the models. Interestingly, in the CLL-prone Eμ-TCL1 model, loss of CD1d expression suppressed spontaneous IgG (but not IgM) production, whereas in the dnRAG1xEμ-TCL1 (DTG) model of accelerated CLL, loss of CD1d expression was associated with elevated numbers of splenic CD4 ⁺and CD8 ⁺T cells and an inverted CD4 ⁺ :CD8 ⁺T cell ratio. Unexpectedly, before leukemia onset, all three transgenic CD1d-deficient mouse strains had fewer splenic transitional B cells than their CD1d-proficient counterparts.

Conclusions

The results show that CD1d expression and iNKT cells are dispensable for the development, accumulation, or IL10 competence of CD5 ⁺B cells in mice prone to benign or leukemic CLL-like B cell expansion, but reveal a novel role for iNKT cells in supporting B cell progression through the transitional stage of development in these animals. These results suggest CD1d-directed therapies to target CLL could be evaded by downregulating CD1d expression with little effect on continued leukemic CD5 ⁺B cell survival. The data also imply that iNKT cells help restrain pro-leukemic CD8 ⁺T cell expansion in CLL, potentially explaining a reported correlation in human CLL between disease progression, the loss of NKT cells, and a paradoxical increase in CD8 ⁺T cells.

【 授权许可】

   
2015 Palmer et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

【 参考文献 】

• [1]Porcelli SA, Modlin RL. The CD1 system: antigen-presenting molecules for T cell recognition of lipids and glycolipids. Annu Rev Immunol. 1999; 17:297-329.
• [2]Brossay L, Jullien D, Cardell S, Sydora BC, Burdin N, Modlin RL et al.. Mouse CD1 is mainly expressed on hemopoietic-derived cells. J Immunol. 1997; 159:1216-24.
• [3]Amano M, Baumgarth N, Dick MD, Brossay L, Kronenberg M, Herzenberg LA et al.. CD1 expression defines subsets of follicular and marginal zone B cells in the spleen: beta 2-microglobulin-dependent and independent forms. J Immunol. 1998; 161:1710-7.
• [4]Yanaba K, Bouaziz J-D, Haas KM, Poe JC, Fujimoto M, Tedder TF. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity. 2008; 28:639-50.
• [5]Kotsianidis I, Nakou E, Spanoudakis E, Bouchliou I, Moustakidis E, Miltiades P et al.. The Diagnostic value of CD1d expression in a large cohort of patients with B-cell chronic lymphoproliferative disorders. Am J Clin Pathol. 2011; 136:400-8.
• [6]Fais F, Morabito F, Stelitano C, Callea V, Zanardi S, Scudeletti M et al.. CD1d is expressed on B-chronic lymphocytic leukemia cells and mediates alpha-galactosylceramide presentation to natural killer T lymphocytes. Int J Cancer. 2004; 109:402-11.
• [7]Bojarska-Junak A, Hus I, Dmoszynska A, Rolinski J. CD1d expression is higher in chronic lymphocytic leukemia patients with unfavorable prognosis. Leuk Res. 2014; 38:435-42.
• [8]DiLillo DJ, Weinberg JB, Yoshizaki A, Horikawa M, Bryant JM, Iwata Y et al.. Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function. Leukemia. 2013; 27:170-82.
• [9]Van Kaer L, Parekh VV, Wu L. Invariant natural killer T cells as sensors and managers of inflammation. Trends Immunol. 2013; 34:50-8.
• [10]Lang ML. How do natural killer T cells help B cells? Expert Rev Vaccines. 2009; 8:1109-21.
• [11]Yang J-Q, Wen X, Kim PJ, Singh RR. Invariant NKT cells inhibit autoreactive B cells in a contact- and CD1d-dependent manner. J Immunol. 2011; 186:1512-20.
• [12]Wermeling F, Lind SM, Jordo ED, Cardell SL, Karlsson MC. Invariant NKT cells limit activation of autoreactive CD1d-positive B cells. J Exp Med. 2010; 207:943-52.
• [13]Shen L, Zhang H, Caimol M, Benike CJ, Chakravarty EF, Strober S et al.. Invariant natural killer T cells in lupus patients promote IgG and IgG autoantibody production. Eur J Immunol. 2015; 45:612-23.
• [14]Takahashi T, Strober S. Natural killer T cells and innate immune B cells from lupus-prone NZB/W mice interact to generate IgM and IgG autoantibodies. Eur J Immunol. 2008; 38:156-65.
• [15]Mendiratta SK, Martin WD, Hong S, Boesteanu A, Joyce S, VanKaer L. CD1d1 mutant mice are deficient in natural T cells that promptly produce IL-4. Immunity. 1997; 6:469-77.
• [16]Hassaballa AE, Palmer VL, Anderson DK, Kassmeier MD, Nganga VK, Parks KW et al.. Accumulation of B1-like B cells in transgenic mice over-expressing catalytically inactive RAG1 in the periphery. Immunology. 2011; 134:469-86.
• [17]Scarfo L, Dagklis A, Scielzo C, Fazi C, Ghia P. CLL-like monoclonal B-cell lymphocytosis: are we all bound to have it? Semin Cancer Biol. 2010; 20:384-90.
• [18]Nganga VK, Palmer VL, Naushad H, Kassmeier MD, Anderson DK, Perry GA et al.. Accelerated progression of chronic lymphocytic leukemia in E mu-TCL1 mice expressing catalytically inactive RAG1. Blood. 2013; 121:3855-66.
• [19]Bichi R, Shinton SA, Martin ES, Koval A, Calin GA, Cesari R et al.. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc Natl Acad Sci U S A. 2002; 99:6955-60.
• [20]Bai L, Constantinides MG, Thomas SY, Reboulet R, Meng F, Koentgen F et al.. Distinct APCs explain the cytokine bias of alpha-galactosylceramide variants in vivo. J Immunol. 2012; 188:3053-61.
• [21]Park SH, Roark JH, Bendelac A. Tissue-specific recognition of mouse CD1 molecules. J Immunol. 1998; 160:3128-34.
• [22]Hobeika E, Thiemann S, Storch B, Jumaa H, Nielsen PJ, Pelanda R et al.. Testing gene function early in the B cell lineage in mb1-cre mice. Proc Natl Acad Sci U S A. 2006; 103:13789-94.
• [23]Matsushita T, Yanaba K, Bouaziz J-D, Fujimoto M, Tedder TF. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest. 2008; 118:3420-30.
• [24]DiLillo DJ, Matsushita T, Tedder TF. B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Ann N Y Acad Sci. 2010; 1183:38-57.
• [25]Bojarska-Junak A, Hus I, Sieklucka M, Wasik-Szczepanek E, Mazurkiewicz T, Polak P et al.. Natural killer-like T CD3+/CD16 + CD56+ cells in chronic lymphocytic leukemia: Intracellular cytokine expression and relationship with clinical outcome. Oncol Rep. 2010; 24:803-10.
• [26]Jadidi-Niaragh F, Jeddi-Tehrani M, Ansaripour B, Razavi SM, Sharifian RA, Shokri F. Reduced frequency of NKT-like cells in patients with progressive chronic lymphocytic leukemia. Med Oncol. 2012; 29:3561-9.
• [27]Weinkove R, Brooks CR, Carter JM, Hermans IF, Ronchese F. Functional invariant natural killer T-cell and CD1d axis in chronic lymphocytic leukemia: implications for immunotherapy. Haematologica. 2013; 98:376-84.
• [28]Hardy RR, Hayakawa K. CD5 B cells, a fetal B cell lineage. Adv Immunol. 1994; 55:297-339.
• [29]Goubier A, Vocanson M, Macari C, Poyet G, Herbelin A, Nicolas JF et al.. Invariant NKT cells suppress CD8(+) T-Cell-mediated allergic contact dermatitis independently of regulatory CD4(+) T cells. J Investig Dermatol. 2013; 133:980-7.
• [30]Ho LP, Urban BC, Jones L, Ogg GS, McMichael AJ. CD4(−)CD8 alpha alpha subset of CD1d-restricted NKT cells controls T cell expansion. J Immunol. 2004; 172:7350-8.
• [31]Han YM, Jiang ZP, Chen ZB, Gu Y, Liu YF, Zhang X et al.. Pathogen-expanded CD11b(+) invariant NKT cells feedback inhibit T cell proliferation via membrane-bound TGF-beta 1. J Autoimmun. 2015; 58:21-35.
• [32]Mellstedt H, Choudhury A. T and B cells in B-chronic lymphocytic leukaemia: Faust, Mephistopheles and the pact with the Devil. Cancer Immunol Immunother. 2006; 55:210-20.