Abstract
Aim:T-helper cells could play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), a common B-cell neoplasm. Although CLL cells can present soluble antigens targeted from the B-cell receptor to T-helper cells via major histocompatibility complex (MHC) class II, antigens recognized by some CLL cells may be encountered in a particulate form. Here the ability of CLL cells to internalize and present anti-immunoglobulin M (IgM) beads as a model for the interaction of CLL cells with particulate antigens was investigated.Methods:The effect of anti-IgM beads on antigen presentation pathways was analyzed using RNA-seq and internalization of anti-IgM beads by primary CLL cells was investigated using confocal microscopy and flow cytometry. Antigen presentation was investigated by analyzing activation of a T-cell line expressing a T-cell receptor specific for a peptide derived from mouse κ light chains after incubating CLL cells with a mouse κ light chain-containing anti-IgM monoclonal antibody. Kinase inhibitors were used to characterize the pathways mediating internalization and antigen presentation.Results:Stimulation of surface IgM of CLL cells increased expression of the antigen presentation machinery and CLL cells were able to phagocytose anti-IgM beads. Internalization of anti-IgM beads was associated with MHC class II-restricted activation of cognate T-helper cells. Antigen presentation by CLL cells was dependent on activity of spleen tyrosine kinase (SYK) and phosphatidylinositol 3-kinase delta (PI3Kδ) but was unaffected by inhibitors of Bruton’s tyrosine kinase (BTK).Conclusions:CLL cells can internalize and present antigen from anti-IgM beads. This capacity of CLL cells may be particularly important for recruitment of T-cell help in vivo in response to particulate antigens.
Highlights
The ability of the B-cell receptor (BCR) to internalize antigen (Ag) for major histocompatibility complex (MHC) class II presentation to CD4+ T helper (Th) cells is critical for generating effective antibody responses [1, 2]
Internalization of anti-immunoglobulin M (IgM) beads was associated with MHC class II-restricted activation of cognate T-helper cells
Antigen presentation by chronic lymphocytic leukemia (CLL) cells was dependent on activity of spleen tyrosine kinase (SYK) and phosphatidylinositol 3-kinase delta (PI3Kδ) but was unaffected by inhibitors of Bruton’s tyrosine kinase (BTK)
Summary
The ability of the B-cell receptor (BCR) to internalize antigen (Ag) for major histocompatibility complex (MHC) class II presentation to CD4+ T helper (Th) cells is critical for generating effective antibody responses [1, 2]. The mechanism by which the BCR internalizes Ag depends on the form of Ag [3,4,5] and B cells were generally considered to have low phagocytic activity, it is recognized that B cells can phagocytose and present particulate Ag, especially when targeted to the BCR [4, 6, 7]. The form of Ag recognized by the BCR has important consequences for shaping immune responses, and particulate Ag elicits potent responses [8, 9]. Several lines of evidence indicate an important role for Th cells in CLL pathogenesis [11]. Th cells are required for growth of CLL cells in xenograft models [15] and factors expressed by Th cells [such as interleukin-4 (IL-4) and CD40L] promote survival and/or proliferation of CLL cells in vitro [16,17,18]
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