In This Issue

Myocardial infarction (MI) is characterized by recruitment of inflammatory leukocytes, including dendritic cells (DCs), to the heart. However, the contribution of specific DC subsets to MI pathology is unknown. Thus, Lee et al. (p. 1784) characterized conventional DC (cDC) subsets in murine healthy and infarcted myocardium to assess the functional impact of DC depletion on ischemic cardiac injury. Healthy hearts contained three DC subpopulations: cDC1s (CD103⁺ CD11b⁻), cDC2s (CD103⁻ CD11b⁺), and double-negative cDCs. Treatment with Flt3 ligand, a DC growth factor, induced cardiac cDC1 numbers, whereas cDC2 cells were largely unaffected. Following coronary artery ligation to induce MI in wild type mice, granulocytes and total DCs increased within the myocardium. Of the DC subsets, CD11b⁺ cDC2s increased most significantly. Moreover, all examined DC subsets displayed signs of activation. Depletion of cDCs following induction of MI led to a significant improvement of left ventricular fractional shortening, a reduction in cardiomyocyte hypertrophy, and a decrease in the infarct size. Moreover, cDC depletion was associated with a reduction in the number of total leukocytes and macrophages in the heart and a decrease in IL-1β and IFN-γ mRNAs, suggesting that cDCs are required for immune cell infiltration. Overall, these studies elucidate the role of cDCs in MI recovery and highlight their pathological role in MI.

Addition of nontemplated (N) regions during Ig gene rearrangement contributes to Ab diversity. However, distinctions in N addition between the V_H and D gene segments (N1) and the D and J_H gene segments (N2) have not been characterized fully. In this issue, Funck et al. (p. 1765) examined the nucleotide composition of N regions in a large dataset consisting of V_HDJ_H rearrangements and DJ_H rearrangements. Whereas the relative distributions of adenine, cytosine (C), guanine (G), and thymine did not differ between N1 and N2 prior to Ag selection and somatic mutation, G and C were not uniformly distributed in the N2 regions, displaying gradients from 5′ to 3′ end over a large range of N2 region lengths. The gradients of G and C were opposites of each other, leading to a significant change in the G/C ratio throughout the N regions. In unmutated productive (P) rearrangements, there was a relative enrichment of G in the N1 region, compared with unmutated nonproductive (NP) rearrangements. In NP V_HDJ_H rearrangements, fewer V_H 3′ ends were trimmed, relative to D 3′ ends and J_H 5′ ends found in NP V_HDJ_H and sterile DJ_H rearrangements. Similarly, the pattern was present in P rearrangements, demonstrating that the N1 region was flanked by an untrimmed gene segment more frequently than N2 and that gene segments were subject to different levels of trimming. G/C gradient remained low closest to trimmed D 3′ ends and high throughout N2 regions if only the J_H end was trimmed, suggesting that the G/C gradient observed in N2 regions depends on the trimming of both flanking gene segments. N1 regions of unmutated NP V_HDJ_H rearrangements that were trimmed at both the V_H gene and the 5′ end of the D gene displayed a similar G/C gradient. These studies demonstrate that the G/C composition and diversity of human Ig N regions depend on the extent by which flanking gene segments are trimmed.

The NADPH-dependent phagocyte oxidase complex (Phox) is known to play a protective role in tuberculosis. However, its function in promoting tolerance to Mycobacterium tuberculosis remains unknown. In this issue, Olive et al. (p. 1705) examined the mechanisms by which Phox contributes to protection from tuberculosis by generating mice lacking the Cybb (gp91) subunit of Phox (Cybb^−/−). Although Cybb^−/− and wild type (WT) mice displayed no significant differences in survival or lung bacterial burden during early infection, the lungs of mutant animals contained larger lesions and increases in neutrophils and IL-1β, which has been shown previously to promote neutrophil-mediated disease in M. tuberculosis–susceptible mouse strains. Cybb^−/− bone marrow–derived macrophages (BMDMs) and bone marrow–derived dendritic cells produced significantly more IL-1β after M. tuberculosis infection, relative to WT cells. The increase in IL-1β was due to enhanced processing of Caspase-1 to its active form, rather than an increase in Il1b mRNA. Therefore, the loss of Cybb leads to hyperactivation of Caspase-1 and subsequent increased release of IL-1β. Inflammasome inhibition in Cybb^−/− BMDMs reduced IL-1β secretion to the same level as WT BMDMs, indicating that increased secretion of IL-1β in Cybb^−/− BMDMs is dependent on inflammasome activation. Inhibition of IL-1 signaling reduced neutrophil infiltration in Cybb^−/− mice to levels observed in WT mice. These studies demonstrate that Phox plays a role in M. tuberculosis immunity by preventing an IL-1–dependent inflammatory response that increases neutrophil recruitment to the lung. Thus, Phox plays a protective role by promoting tolerance to M. tuberculosis, rather than exerting a direct antimicrobial effect.

Immunocompromised individuals lacking CD4⁺ T cells are susceptible to life-threatening fungal infections. Efforts to develop an effective fungal vaccine that elicits a potent CD8⁺ T cell response in the absence of CD4⁺ T cell help have been unsuccessful. In this issue, Nanjappa et al. (p. 1717) sought to determine if reduction of the TCR signaling threshold via ablation of Casitas B–lymphoma-b (CBLB), an E3 ubiquitin ligase that negatively regulates T cell signaling, could enhance CD8⁺ T cell responses to fungal vaccines in the absence of CD4⁺ T cells. Vaccination of CBLB-deficient (Cblb^−/−) mice with a live attenuated yeast vaccine significantly increased the frequency and numbers of both type 1– and type 17–producing CD8⁺ T cells in the spleen and lymph nodes when compared with CBLB-sufficient mice. Similarly, CBLB deficiency enhanced both type 1 and type 17 CD8⁺ T cell responses to inactivated fungal vaccines. Cblb^−/− mice immunized with inactivated vaccines were also protected from lethal pulmonary challenge. Ablation of CBLB had no impact on CD8⁺ T cell terminal differentiation or the expression of transcription factors T-bet, Eomes, and RORγt; rather, CBLB deficiency increased production of IFN-γ and IL-17A following vaccination with inactivated yeast. In addition, adoptive transfer experiments showed that the effect of CBLB ablation on antifungal CD8⁺ T cell responses was cell intrinsic. Finally, the authors found that CBLB deficiency overcomes the requirement for hypoxia-inducible factor-1α, which was previously found to be necessary for the expansion of antifungal CD8⁺ T cells. Together, these studies demonstrate that modulation of TCR signaling via ablation of CBLB augments type 1 and type 17 cytokine–producing CD8⁺ T cell responses, which may provide protection from lethal fungal pneumonia in individuals lacking CD4⁺ T cells.