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

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 IFNc on CD3-stimulated CD4 ? T cells from CLL patients, similarly in T cells from ZAP-70 ? to ZAP-70patients. Autologous nurse-like cells establish a close contact with CD4 ? T cells and increase their activation and proliferation partially through a CXCR4dependent 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.

Chronic lymphocytic leukaemia cells become both activated and immunosuppressive following interaction with CD3 and CD28 stimulated PBMC

“…This provides another layer of potential interaction between CLL cells and T-cells within the tumour microenvironment. Increasing evidence has underlined the importance of reciprocal CLL T-cell activation in providing signals for CLL progression [10][11][12][13][14][15][16], and the results of the current study raise the possibility that CLL cells, once sufficiently stimulated by T-cell activation are then capable of limiting further T-cell responses.…”

“…Within this micro-environment activated Tcells co-localise with activated proliferating CLL cells. This, together with data showing that activated T-cells or their associated signals (CD40L/cytokines) can induce CLL activation, proliferation and survival, suggests that this interaction is important in CLL progression [10][11][12][13][14][15][16]. Although circulating CLL cells have been shown to be capable of inducing functional defects in T-cells [3,[5][6][7], it is unclear whether the activated CLL cells generated following interaction with activated T-cells are able to modulate or suppress subsequent T-cell responses.…”

“…Numerous studies have demonstrated that stimulation of CLL cells with either activated T-cells or their associated signals (CD40L, cytokines) can induce CLL proliferation, altered gene expression and resistance to apoptosis [10][11][12][13][14][15][16]. Studies on the immunoregulatory capacity of activated CLL have however been limited to the demonstration that cytokine or CD40L activated CLL cells have increased expression of co-stimulatory molecules and acquire the ability to stimulate T-cell responses [17][18][19].…”

“…Interaction with autologous activated T-cells has been reported to induce CLL activation which is associated with increased size, HLA-DR and CD38 expression [12,13,16,26]. In order to determine the effect of interaction with normal donor PBMC on CLL activation, CLL cells were cultured under different conditions as outlined in Fig.…”

The Expression of Sphingosine-1 Phosphate Receptor-1 in Chronic Lymphocytic Leukemia Cells Is Impaired by Tumor Microenvironmental Signals and Enhanced by Piceatannol and R406

“…NLC cocultures. In vitro NLC differentiation was performed as previously described (7,32). Briefly, 5 3 10 6 freshly purified PBMCs from CLL patients were cultured in 1 ml complete medium (RPMI 1640 supplemented with 10% FCS, 100 U/ml penicillin, and 100 mg/ml streptomycin) in a 24-well cell culture plate for 14 d. Then, nonadherent cells were isolated, whereas attached NLCs were used for the following experiments.…”