In This Issue

Dimethyl fumarate (DMF) is an approved treatment for multiple sclerosis and has been shown to be effective in treating other autoimmune diseases; however, its mechanism of action is poorly understood. In this issue, Zaro et al. (p. 2737) identified a mechanism by which DMF inhibits plasmacytoid dendritic cell (pDC) function through targeting IRAK4. Previous studies have shown that DMF can activate the NRF2–KEAP1 pathway, but in this article the authors show that DMF can inhibit pDC cytokine responses independent of NRF2. They used a chemical proteomics screen to find cysteine residues in pDCs that were sensitive to DMF activity and identified cysteine 13 (C13) in IRAK4 as being highly sensitive. They went on to show that DMF can block IRAK4 interactions with MyD88 by targeting C13, and this, in turn, blocks IRAK4-driven cytokine production. These data reveal how DMF can target cytokine production in pDCs, which in turn may provide insight into its therapeutic effects on autoimmune disorders.

Monocytes and macrophages play multiple roles in skin repair and wound healing. In this regard, IL-1R1 signaling has been linked to such repair responses. In this issue, Barman et al. (p. 2720) examine the role of monocyte expansion in response to skin wounding. They observe that skin wounding promotes expansion of several progenitor subsets from the myeloid lineage, particularly the multipotent progenitor subset MPP3 and monocytes. IL-1R1 is not required for this expansion or for monocyte differentiation induced by M-CSF. Although IL-1R1–deficient mice showed a delay in skin wound healing, this was attributed to a higher frequency of Ly6C^lo monocytes at the onset of skin wounding. Together, these results reveal a critical role for monocyte expansion during skin wound healing that is exclusive of IL-1R1 signaling.

Surfactant protein-C (SP-C) is associated with idiopathic pulmonary fibrosis (IPF) in both children and adults. Venosa et al. (p. 2760) have developed a mouse model with an inducible point mutation of SP-C (SP-C^I73T) to study the early immunological events involved in IPF. Two weeks after induction of SP-C^I73T, an increase in cellular infiltrate was detected in both bronchoalveolar lavage fluid (BALF) and lung tissue. These cells primarily consisted of peripheral monocytes. The researchers also noted that there was a shift in macrophage polarization toward an anti-inflammatory phenotype. Depleting peripheral monocytes led to an increased survival rate and a decrease in cellular influx to the lungs. Additionally, i.v. clodronate decreased the number of immature macrophages in the lung and BALF, and also led to an increased survival of the animals. These data provide a glimpse into the early inflammatory cascade of IPF and a role for peripheral macrophages in this process.

Cytotoxic T lymphocyte-associated Ag 4 expression on B cells in chronic lymphocytic leukemia (CLL) is positively associated with disease progression. In this issue, Do et al. (p. 2806) found that CLL B cells produced CTLA-4 protein, but it was not expressed on the cell surface until coculture with activated T cells. CLL cells expressing CTLA-4 were able to bind soluble CD80, as well as transfer CD80, through trans-endocytosis, to the CLL cells. This process was inhibited by the CTLA-4 blocking Ab ipilimumab. In MLCs, downregulation of CD80 was shown to affect T cell expression of IL-2. Finally, a murine model of CLL was devised that used transfer of CLL cells expressing murine CTLA-4 (mCTLA-4) into a humanized mouse, with T cells expressing human CTLA-4. An Ab was created that could specifically block CTLA-4 in CLL without affecting T cell expression of the molecule. When mice were treated with the anti–mCTLA-4 Ab, they showed a significant decrease in leukemic burden after 34 d. This new role for tumor-expressed CTLA-4 could help drive development of the next stage of targeted cancer therapies.

CD4⁺ T cells differentiate into distinct subsets based on TCR affinities for peptide:MHC class II (p:MHCII) complexes presented on dendritic cells (DCs). In this issue, Kotov et al. (p. 2535) examine mechanisms of this commitment process using two TCR transgenic mouse strains with different binding affinities for the same peptide (P5R). Mice were challenged with either an influenza virus or a Listeria monocytogenes strain engineered to express the P5R epitope. The authors found that naive T cells with high-affinity TCRs were biased toward Th1 and Th17 fate, whereas low-affinity TCRs were biased toward a T follicular helper (Tfh) cell fate. Although researchers found that XCR1⁺ DCs and SIRPα⁺ DCs are critical for optimal Th1 and Tfh differentiation, respectively, T cell/DC interaction alone did not account for T cell subset differentiation. Instead, TCR affinity influenced IL-2Rα (CD25) expression, such that high-affinity interactions maintain CD25 expression and promote Th1, which was also associated with expression of the eukaryotic translation elongation factor 1 ε 1. In contrast, guanylate binding protein 2 expression was associated with inhibition of Th1 differentiation. Together, these data provide deeper mechanistic insights into how TCR affinity shapes Th cell differentiation.

The DQ allele of MHC class II (MHCII) is associated with an increased incidence of celiac disease, as well as poor responses to several vaccines. In this issue, Hung et al. (p. 2558) investigate how the interaction of HLA-DQ (DQ) with HLA-DM (DM), a catalyst/chaperone responsible for epitope editing and stabilizing MHCII, plays a role in the onset of celiac disease. The researchers used human APCs engineered to express high levels of DM and only the DQ allele of MHCII to test how the gluten epitope gliadin is presented. They demonstrated that increased expression of DM in APCs led to a decrease in gliadin presentation and an attenuated T cell response, compared with the DM^null APCs. Additionally, a point mutant of DQ, which has higher affinity to DM than the wild type, showed similar decreased T cell response to gliadin. T cell responses to gliadin increased when gliadin was exogenously loaded into DQ, bypassing the intracellular interaction with DM. Additionally, viral Ag presentation and T cell response were enhanced when APCs expressed higher levels of DM. When DQ/DM interactions were enhanced because of the overexpression of DM or a point mutation in DC, the DQ epitopes undergo DM editing. In the case of gliadin, DM editing resulted in a lower affinity epitope and a diminished T cell response. Alternatively, viral epitopes increased their affinity to DQ, resulting in more robust T cell responses. These data show that increased expression levels of DM in APCs may benefit tolerance and enhance presentation of pathogen-derived epitopes.