CD8α+ DC differentiation

There are several subsets of dendritic cells (DCs), each with its own functional specialty. In Blood, Rothman and colleagues investigate the differentiation of one of these subsets: CD8α+ DCs. The leucine zipper transcription factor E4BP4 is known chiefly for its influence on the circadian rhythm and for its role in natural killer cell differentiation. The authors observe that the various DC subsets all have high expression of E4BP4. E4BP4-deficient (Nfil3−/−) mice lack CD8α+ DCs but have normal frequencies of CD8α− DCs and plasmacytoid DCs, which indicates a selective developmental defect. Attempts to differentiate CD8α− DCs from Nfil3−/− mice in vitro or in vivo with the stimulatory cytokine Flt3L all fail. Functionally, CD8α+ DCs are required for antigen cross-presentation; consistent with their absence, Nfil3−/− mice have impaired cross-presentation. The precise action of E4BP4 is unclear, but it seems to act in part via the transcription factor BATF. ZF

Blood 117, 6193–6197 (2011)

Growing it local

A key feature of tissue inflammation is the recruitment of cells of the innate immune system from the blood, whereas proliferation in situ is generally not thought to be of major importance. In Science, Allen and colleagues investigate the proliferation of tissue macrophages after infection with nematodes, a strong driver of type 2 inflammation. Among other features of type 2 inflammation is expression of the cytokines IL-4 and IL-13 and the differentiation of macrophages into an alternatively activated M2 phenotype. Nematode infection not only triggers the M2 differentiation of recruited monocytes or tissue macrophages already present but also elicits substantial proliferation of these cells in situ. The proliferation of tissue macrophages can be similarly triggered by administration of IL-4 and is dependent on intact IL-4 signaling. Proliferation of macrophages in situ thus diminishes the need for a circulating pool of monocyte precursors or the energetic demands that accompany mobilization from the bone marrow. ZF

Science 332, 1284–1288 (2011)

Stem cells and Treg cells

Specialized microenvironmental niches provide appropriate support for the maintenance and differentiation of adult stem cells. In Nature, Lin and colleagues show that regulatory T cells (Treg cells) provide active immunoregulation of the hematopoietic stem cell (HSC) niche in the bone marrow. Transplanted HSCs survive long term in the bone marrow of unirradiated syngeneic and allogeneic recipients without immunosuppression. In vivo imaging and histological analyses show the preferential localization of Treg cells on the endosteal surface of the skull bone marrow and trabecular bone marrow of long bones, in very close proximity to HSCs. Depletion of Treg cells results in fewer surviving donor HSCs in unirradiated recipients. Immunoprotection depends on the soluble factor interleukin 10 (IL-10) but is independent of the secretion of transforming growth factor-β from Treg cells. Thus, discrete sites of immune privilege may exist and contribute to somatic stem cell niches. IV

Nature 474, 216–219 (2011)

CD28 sustains plasma cells

Protective lifelong immunity often requires sustained antigen-specific antibody production, yet whether this depends on long-lived plasma cells that continuously produce antibody or the new generation of plasma cells triggered by persistent antigen presentation is unclear. In the Journal of Experimental Medicine, Lee and colleagues show that long-lived plasma cells form a distinct subset of antibody-producing cells that exist in the bone marrow of immunized mice. Plasma cell expression of the costimulatory marker CD28 is essential for mediating longevity in the bone marrow niche. Stromal or DC expression of both CD28 ligands, CD80 and CD86, is necessary, which suggests a nonredundant function for these molecules in supporting the survival of long-lived plasma cells. Surprisingly, short-lived splenic plasma cells also express CD28, but these cells seem to have differences in their signaling response to CD28 ligation. What these differences are and how they contribute to plasma cell lifespan remain unknown. LAD

J. Exp. Med. (20 June 2011) doi:10.1084/jem.20110040

TFH programs

The transcription factor Bcl-6 is a critical regulator of the differentiation of follicular helper T cells (TFH cells); however, the mechanisms that control its expression remain unclear. In addition, assessment of cell-autonomous events linked to TFH differentiation is further complicated by the requirement for B cell interactions. In Immunity, Choi et al. show that commitment to the TFH lineage and Bcl-6 induction is B cell independent and is 'instructed' by DC interactions, whereas the late maintenance of TFH cells and of Bcl-6 expression depends on interactions with B cells. Signaling by the inducible costimulator ICOS is required during both the DC− and B cell-dependent stages. In vivo, a TFH differentiation program characterized by the expression of Bcl-6 and the chemokine receptor CXCR5 can be identified within the first two cell divisions and antagonizes the CD4+ T cell effector program, characterized by high expression of the IL-2 receptor α-chain and early induction of the transcription factor Blimp-1. IV

Immunity 34, 932–946 (2011)

Aiding tolerance

Activation-induced cytidine deaminase (AID) mediates the diversification of immunoglobulin genes in activated mature B cells. In the Proceedings of the National Academy of Science, Kuraoka et al. identify a role for AID in establishing central tolerance in immature B cells. Transitional B cells have low but detectable expression of AID. Mice lacking AID (Aicda−/−) have higher serum titers of autoantibodies. Over-representation of Aicda−/− immature B cells, but not of other hematopoietic lineages, arises in mixed chimeric mice reconstituted with equal portions of wild-type and Aicda−/− bone marrow, which suggests a competitive advantage. Similarly, more immature transitional B cells are present in Aicda−/− mice bearing 3H9 immunoglobulin transgenes, which encode self-reactive antibodies. Wild-type 3H9-transgenic B cells express less AID message than do nontransgenic control B cells, yet 3H9-transgenic mice have higher frequencies somatic mutations in their immunoglobulin genes. How self-reactive B cell antigen receptor signaling leads to AID-mediated central tolerance remains somewhat mysterious. LAD

Proc. Natl. Acad. Sci. USA (23 June 2011) doi:10.1073/pnas.1102571108