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CXCL12 is a costimulator for CD4+ T cell activation and proliferation in chronic lymphocytic leukemia patients

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Abstract

Activated T cells from patients with chronic lymphocytic leukemia (CLL) provide survival and proliferative signals to the leukemic clone within lymphoid tissues. Recruitment of both, CLL cells and T lymphocytes, to this supportive microenvironment greatly depends on CXCL12 production by stromal and myeloid cells. CXCL12 also supplies survival stimuli to leukemic B cells, but whether it exerts stimulatory effects on T lymphocytes from CLL patients is unknown. In order to evaluate the capacity of CXCL12 to increase CD4+ T cell activation and proliferation in CLL patients, peripheral blood mononuclear cells were cultured with or without recombinant human CXCL12 or autologous nurse-like cells, and then T cell activation was induced by anti-CD3 mAb. CXCL12 increases the proliferation and the expression of CD25, CD69, CD154, and IFNγ on CD3-stimulated CD4+ T cells from CLL patients, similarly in T cells from ZAP-70+ to ZAP-70− patients. Autologous nurse-like cells establish a close contact with CD4+ T cells and increase their activation and proliferation partially through a CXCR4-dependent mechanism. In addition, we found that activated T cells in the presence of CXCL12 enhance the activation and proliferation of the leukemic clone. In conclusion, CXCL12 production by lymphoid tissue microenvironment in CLL patients might play a key dual role on T cell physiology, functioning not only as a chemoattractant but also as a costimulatory factor for activated T cells.

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Acknowledgments

The authors would like to thank Beatriz Loria and Edit Mabel Horvat for technical assistance. We also thank CLL patients who participated in the study. This work was supported by grants from Agencia Nacional de Promoción Científica y Tecnológica, CONICET and Fundación Roemmers. M. B. designed and did experiments and created the figures; P. R. N. and P. E. M contributed in the analysis and interpretation of the data; C. J. contributed in the analysis and interpretation of the data and collaborated in confocal microscopy assay; R. F. B. and A. B. provided patients samples and advice; M. G. participated in the project conception and critically reviewed the manuscript, which was written by M. B. and R. G.; R. G. designed and supervised the study.

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The authors reported no potential conflicts of interest.

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Authors and Affiliations

  1. Laboratorio de Inmunología Oncológica, Instituto de Medicina Experimental (IMEX) - CONICET, Academia Nacional de Medicina, Pacheco de Melo 3081 (1425), Ciudad de Buenos Aires, Argentina

    Mercedes Borge, Paula Romina Nannini, Pablo Elías Morande, Carolina Jancic, Mirta Giordano & Romina Gamberale

  2. Hospital J. M. Ramos Mejía, Ciudad de Buenos Aires, Argentina

    Alicia Bistmans

  3. Hospital General de Agudos Dr. T. Álvarez, Ciudad de Buenos Aires, Argentina

    Raimundo Fernando Bezares

  4. Departamento de Microbiología Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina

    Mercedes Borge, Paula Romina Nannini, Pablo Elías Morande, Carolina Jancic, Mirta Giordano & Romina Gamberale

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  1. Mercedes Borge
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  2. Paula Romina Nannini
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Correspondence to Romina Gamberale.

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Borge, M., Nannini, P.R., Morande, P.E. et al. CXCL12 is a costimulator for CD4+ T cell activation and proliferation in chronic lymphocytic leukemia patients. Cancer Immunol Immunother 62, 113–124 (2013). https://doi.org/10.1007/s00262-012-1320-7

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  • DOI: https://doi.org/10.1007/s00262-012-1320-7

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