Chronic Lymphocytic Leukemia Cells Are Activated and Proliferate in Response to Specific T Helper Cells

Abstract

There is increasing interest in the chronic lymphocytic leukemia (CLL) microenvironment and the mechanisms that may promote CLL cell survival and proliferation. A role for T helper (Th) cells has been suggested, but current evidence is only circumstantial. Here we show that CLL patients had memory Th cells that were specific for endogenous CLL antigens. These Th cells activated autologous CLL cell proliferation in vitro and in human → mouse xenograft experiments. Moreover, CLL cells were efficient antigen-presenting cells that could endocytose and process complex proteins through antigen uptake pathways, including the B cell receptor. Activation of CLL cells by Th cells was contact and CD40L dependent. The results suggest that CLL is driven by ongoing immune responses related to Th cell-CLL cell interaction. We propose that Th cells support malignant B cells and that they could be targeted in the treatment of CLL.

Chronic Lymphocytic Leukemia Cells Express CD38 in Response to Th1 Cell–Derived IFN-γ by a T-bet–Dependent Mechanism

“…Very recently, we found that CLL patients had Th1-like cells that responded to endogenous CLL cell Ag presented by CLL cells on HLA class II molecules (11). Such Th cells supported the activation and expansion of CLL cells in vitro and in xenografted mice.…”

“…The transcription factor T-bet is the key regulator in Th1 cell polarization and type 1 immune responses (15) and has also been detected in CLL cells (11,16). In murine B cells, T-bet plays a role in B cell migration (17) and is essential for class switch to IgG2a and for IFN-g production (15,18,19).…”

“…To study Ag-dependent Th1 cell-CLL cell interaction, we use a human Th1 cell clone (T18) specific for an epitope in the mouse Ig k-chain, when presented on the MHC class II haplotype (HLA-DRB1*0401) (11). This Th1 cell clone is not related to CLL but allows functional studies of Agdependent cognate interaction with Th cells.…”

“…A total of 1500 ng biotin-labeled cRNA was used to hybridize onto Illumina HumanWG-6 v3 Expression BeadChips. Gene expression profiling was performed as reported (11). Analysis was performed using GeneSpring GX v11 software (Agilent, Santa Clara, CA).…”

Spleen tyrosine kinase inhibitors reduce CD40L-induced proliferation of chronic lymphocytic leukemia cells but not normal B cells

“…4,5 Several studies suggest that CLL cells are rescued by combined BCR and CD40L triggering; an anti-apoptosis, activation and differentiation signal is mediated by T helper (Th) cells via CD40L (CD40 ligand, CD154) that binds CD40 on the B cell surface. [6][7][8][9][10] Thus, CLL patients have CLL-specific Th cells that can support CLL cell proliferation in xenografts, 8,9 activated CD40L + Th cells colocalize with proliferating CLL cells in pseudofollicles, 6,7 and CLL cells secrete Th attracting chemokines, thereby recruiting T cell help. 6,9 It has been unclear how BCR pathway inhibitors impact the microenvironmental help of CLL cells.…”