In This Issue

doi:10.4049/jimmunol.1490038

Genetic Variability of Mice and Men

The Mouse Phenome Database Project and the Immunological Genome Project (IGP) collect and standardize phenotypic and genotypic data of common laboratory mouse strains to maximize the utility of laboratory mice in biomedical and immunological research. These initiatives also serve to provide justification for using mice to model human disease. Working as part of these two initiatives, Mostafavi et al. (p. 4485) dissected the genetic blueprints of CD4⁺ T cells (T4s) and neutrophils (GNs) from 35 common laboratory strains and 4 wild-derived mouse strains. Using a variety of genomic analysis tools, they examined the extent and distribution of genetic variation across mouse strains and found variability in the expression levels of 58% of tested transcripts. These analyses also revealed 67 loci in T4 cells and 53 loci in GN cells with complete loss of function in some strains, showing that several strains may be used as natural knockouts. To identify genomic regulatory elements that could affect variability in gene expression, the authors examined cis-acting expression quantitative trait loci and found 1,222 of these loci that were likely to be involved in either T4 or GN genetic variation. Comparison of these data with a parallel data set from ethnically diverse humans demonstrated that highly variable genes in mice often correlated with those found in humans, suggesting that variability in certain genes is conserved across species. Together, these data provide insight into the effects of genetic variation on the mouse immune system and provide a documented foundation that rationalizes the use of mice as a model for the study of human disease.

DC Bcl-3 Promotes T Cell Priming

Bcl-3 is an IκB family member that regulates NF-κB-dependent gene expression through a mechanism that involves binding to p50 or p52 homodimers; however, the cellular and biological functions of Bcl-3 have not been thoroughly studied. In this issue, Tassi et al. (p. 4303) explored the role of Bcl-3 in regulating CD11c⁺ dendritic cell (DC) functions and found that specifically ablating this gene in CD11c⁺ cells resulted in a decrease in both priming of CD4⁺ T cells and cross-priming of CD8⁺ T cells in both in vitro and in vivo Ag stimulation models. In a CD8⁺ T cell-dependent contact hypersensitivity model, mice with CD11c-specific Bcl-3 ablation (Bcl-3-∆-DC) had significantly reduced inflammatory responses, suggesting defective cross-priming of CD8⁺ T cells. Mechanistically, Bcl-3 was found to contribute to the survival of DCs, most likely by inhibiting expression of proapoptotic genes. Intravenous LPS injection into Bcl-3^−/− mice or Bcl-3-∆-DC mice led to more pronounced activation-induced cell death in DCs in these mice compared with those in treated wild-type mice, a result confirmed by increased TUNEL staining of spleen sections from LPS-treated Bcl-3-∆-DC mice. Conversely, relative to wild-type DCs, overexpression of Bcl-3 in DCs caused increased DC survival and enhanced T cell priming. Collectively, these data reveal a critical role for Bcl-3 in DC survival that profoundly impacts the effectiveness of DC T cell priming.

Hyperglycemic RAGE

Hyperglycemia resulting from diabetes mellitus can have devastating long-term side effects, including enhanced susceptibility to infection. Martinez et al. (p. 4457) now examine how hyperglycemia influences T cell responses in the absence of infection. T cells from chronically hyperglycemic (HG) mice produced higher levels of Th1, Th2, and Th17 cytokines and showed an accelerated proliferative response relative to T cells from control euglycemic mice following ex vivo anti-CD3ε or Ag stimulation. Chromatin decondensation was increased in naive T cells from HG mice compared with controls. Together, these results suggested that naive T cells from HG mice functioned more like Ag-experienced T cells, although CD44 expression was not elevated in these naive T cells. Chromatin decondensation in T cells from HG mice was linked to expression of the receptor for advanced glycation end products (RAGE), which was most likely induced by elevated levels of endogenous RAGE ligands, including glycated, high mobility group box 1, and S100 proteins. T cells adoptively transferred from HG mice into euglycemic hosts showed intrinsic hyperresponsiveness to TCR stimulation and greater chromatin decondensation, consistent with in vitro observations. Together, these results indicate that chronic hyperglycemia triggers RAGE-mediated epigenetic changes of naive T cells and an altered T cell response, offering a potential mechanism of pathological inflammation in diabetes.

ELLegant Elongator

B cells undergo considerable changes as they differentiate into Ab-secreting cells, and a discrete group of transcription factors drives this differentiation. Park et al. (p. 4663) examined the roles that the transcription elongation factor ELL2 (eleven nineteen lysine-rich leukemia gene), known to influence Igh mRNA processing, plays during B cell differentiation. They created two different B cell–specific CD19cre-driven conditional ELL2 knockout mouse strains with the ELL2 gene floxed in either exon 1 or exon 3. Two different regions were targeted because of concerns that loxp insertion into the promoter region in exon 1 could affect ELL2 expression in other cell types. Relative to controls, both conditional knockout (cKO) strains had lower baseline levels of secreted Abs, as well as limited primary and recall humoral responses to either a T-dependent or T-independent Ag. Immunized cKO mice had higher percentages of immature and recirculating B cells in the bone marrow and fewer splenic transitional B cells and plasma cells relative to immunized controls. Ex vivo LPS stimulation of resting splenic B cells from both cKO strains induced significantly fewer CD138⁺B220^lo plasma cells than in controls; very little Igh was detected in cKO B cells and the endoplasmic reticulum appeared distended and abnormal. cKO mice also had reduced mRNA levels of Igκ L chain, BCMA, and Ig chaperones and activators involved in the unfolded protein response that is critical for production of high levels of Igh. Together, these results highlight the multiple and diverse roles played by ELL2 to support the differentiation of Ab-secreting cells.

Restricted T Cells Promote Pemphigus

Pemphigus vulgaris (PV) is a debilitating autoimmune disease of the skin characterized by the presence of IgG autoantibodies to desmoglein 3 (Dsg3), an element of the desmosomal adhesion complex that is essential for epidermal keratinocyte adhesion. Genetic association studies have identified the HLA allele HLA-DRB1*04:02 as a risk factor for PV, but it is not yet known whether expression of this molecule on immune cells plays a causal role in the generation of IgG autoantibody responses in PV. To explore this possibility, Eming et al. (p. 4391) created a humanized transgenic mouse that expressed a single MHC molecule, HLA-DRB1*04:02 (Tg). They found that immunization of Tg mice with human Dsg3 led to robust production of Dsg3-specific pathogenic IgG autoantibodies. Injection into human skin biopsies of sera from Dsg3-immunized Tg mice, but not sera from immunized mice expressing a non-PV associated HLA gene, resulted in the generation of anti-epithelial cell surface IgG deposits and loss of intraepidermal adhesion, a hallmark symptom of PV. Treating Tg mice with anti-CD4 or anti-CD40L monoclonal Abs in combination with human Dsg3 immunization abrogated anti-Dsg3 IgG Ab production, suggesting that interactions between B cells and T cells were crucial to autoantibody generation. T cells from Tg mice were tightly restricted to HLA-DRB1*04:02, and only peptides binding to HLA-DRB1*04:02 elicited anti-Dsg3 autoantibody responses. These data indicate that T cell recognition of HLA-DRB1*04:02–restricted Dsg3 epitopes plays an integral role in the generation of autoantibody responses in a model of PV and present a potential therapeutic target for the treatment of this disease.

Losing Control in the Mucosa

Chronic SIV infection is associated with increased expression of inhibitory receptors like PD-1 on T cells and impairment of antiviral functions. In vivo blockade of PD-1 during SIV infection restores antiviral functions in CD8⁺ T cells and reduces viral loads. Mylvaganem et al. (p. 4527) now examine how PD-1 expression on CD4⁺ T cells influences chronic SIV infection. PD-1^hi CD4⁺ T cells were detected in the rectal mucosa and lymph nodes (LNs), preferential sites of SIV replication, in naive rhesus macaques (RMs). PD-1^hi CD4⁺ T cells at these sites coexpressed the T follicular helper cell markers CXCR5 and Bcl-6. The frequency of PD-1^hi CD4⁺ T cells as a percentage of total CD4⁺ T cells increased in the rectal mucosa and LNs of SIV-infected noncontrollers (>10⁴ SIV RNA copies/ml of plasma at 24 wk p.i., including unvaccinated and vaccinated animals) relative to SIV-naive or vaccine-controllers (<10⁴ RNA copies/ml of plasma at 24 wk p.i.). Moreover, these PD-1^hi CD4⁺ T cells expressed low levels of the viral coreceptor CCR5 but were able to support viral replication in the rectal mucosa. In contrast, higher levels of granzyme B⁺ SIV tetramer⁺CD8⁺ T cells were detected in the LNs of controllers versus noncontrollers and correlated inversely with the frequency of CXCR5⁺PD-1^hi CD4⁺ T cells. Together these results suggest that PD-1^hi CD4⁺ T cells in the rectal mucosal sites contribute to SIV replication and the antiviral CD8⁺ T cell population may be able to curb the expansion of PD-1^hi CD4⁺ T cells and limit viral replication in the LNs.