Key Points Monocytic IDOhi MDSCs are increased in CLL patients, suppress T cells, and promote TReg induction. CLL cells induce conversion of monocytes into MDSCs suggesting bidirectional crosstalk between CLL cells, MDSCs, and TRegs.

Activation-induced cytidine deaminase (AID) is necessary for immunoglobulin somatic hypermutation (SHM) and class switch recombination (CSR) in T-dependent immune response in germinal centers (GCs). The structural similarity of AID with RNA-editing enzymes and its largely cytoplasmic location have fueled controversial views of its mode of interaction with DNA. We show that AID, a mature B-cell-restricted cytoplasmic antigen, is relocated into the nucleus in 2.5% of IntroductionThe host immune response to foreign antigens in higher vertebrates has evolved via separate cell lineages, such as immunoglobulin-producing B cells, effectors T cells, and a variety of accessory cells specialized in antigen processing and presentation (antigen-presenting cells, APCs). B cells can produce antigen-specific antibodies without (T independent, TI) or with (T dependent, TD) T-cell help. 1 The latter response is characterized by a process of progressive refinement of the antibody by selecting the type of immunoglobulin heavy chain (class switch recombination, CSR) and improving the affinity of the antigen-binding site (affinity maturation). This process entails genetic alterations of the DNA sequences of the immunoglobulin genes, excision of intervening heavy-chain sequences in CSR, and mutation of nucleotides in the antigen-binding region (somatic hypermutation, SHM), a process followed by selection and resulting in affinity maturation. SHM and CSR take place in a lymphoid structure called the germinal center (GC). Typically, cognate T-B interactions with APC and antigen occur at the border of primary lymphoid follicles. 2 Then, antigen-stimulated B cells enter the GC and experience a proliferative burst, mostly with unmutated Ig genes, [3][4][5] followed by the onset of SHM and CSR, resulting in clonal selection of class-switched B cells carrying multiple mutations of their high-affinity antibodies. 3,4,[6][7][8] Transit of GC centroblasts from the dark zone to the light zone of the GC may signal 2 different phases of the generation and selection of high-affinity Ig-carrying B cells. 9,10 The TI response in mice is typically extrafollicular, 11 unmutated, 12 and with no or short transit through a GC reaction. [13][14][15] Recently, evidence of hypermutated memory B cells without GC transit has been identified in humans 16,17 and mice. 14 The gene expression changes that occur from the initial activation up to the GC exit have been extensively described. [18][19][20] Genetic experiments have shown that activation-induced cytidine deaminase (AID) is essential for both CSR and SHM. 21 AID is a 24-kDa molecule of the APOBEC family, 22 restricted in its expression to lymphoid organs 22 and embryonic stem cells. 23 Two separate domains of the AID molecule are required for CSR and SHM, in cooperation with the DNA repair machinery. 24 The mechanism by which AID performs SHM and CSR has been a matter of controversy and is not yet resolved. The structural similarity with the APOBEC family, an RNA-editing enzyme group of proteins, and ot...

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