Mycobacterium tuberculosis is recognized by multiple pattern recognition receptors involved in innate immune defense, but their direct role in tuberculosis pathogenesis remains unknown. Beyond TLRs, scavenger receptors (SRs) and C-type lectins may play a crucial role in the sensing and signaling of pathogen motifs, as well as contribute to M. tuberculosis immune evasion. In this study, we addressed the relative role and potential redundancy of these receptors in the host response and resistance to M. tuberculosis infection using mice deficient for representative SR, C-type lectin receptor, or seven transmembrane receptor families. We show that a single deficiency in the class A SR, macrophage receptor with collagenous structure, CD36, mannose receptor, specific ICAM-3 grabbing nonintegrin-related, or F4/80 did not impair the host resistance to acute or chronic M. tuberculosis infection in terms of survival, control of bacterial clearance, lung inflammation, granuloma formation, and cytokine and chemokine expression. Double deficiency for the SRs class A SR types I and II plus CD36 or for the C-type lectins mannose receptor plus specific ICAM-3 grabbing nonintegrin-related had a limited effect on macrophage uptake of mycobacteria and TNF response and on the long-term control of M. tuberculosis infection. By contrast, mice deficient in the TNF, IL-1, or IFN-γ pathway were unable to control acute M. tuberculosis infection. In conclusion, we document a functional redundancy in the pattern recognition receptors, which might cooperate in a coordinated response to sustain the full immune control of M. tuberculosis infection, in sharp contrast with the nonredundant, essential role of the TNF, IL-1, or IFN-γ pathway for host resistance to M. tuberculosis.

Naked mole‐rats express many unusual traits for such a small rodent. Their morphology, social behaviour, physiology, and ageing have been well studied over the past half‐century. Many early findings and speculations about this subterranean species persist in the literature, although some have been repeatedly questioned or refuted. While the popularity of this species as a natural‐history curiosity, and oversimplified story‐telling in science journalism, might have fuelled the perpetuation of such misconceptions, an accurate understanding of their biology is especially important for this new biomedical model organism. We review 28 of these persistent myths about naked mole‐rat sensory abilities, ecophysiology, social behaviour, development and ageing, and where possible we explain how these misunderstandings came about.

The naked mole rat (Heterocephalus glaber, NMR) is a rodent with exceptional longevity, low rates of age-related diseases and spontaneous carcinogenesis. The NMR represents an attractive animal model in longevity and cancer research, but there are no NMRspecific antibodies available to study its immune system with respect to age-and cancerrelated questions. Substantial homology of major NMR immune cell markers with those of Guinea pig, human and, to a lesser extent, mouse and rat origin are implicated for the existence of immunological cross-reactivity. We identified 10 antibodies recognising eight immunophenotypic markers expressed on the NMR's T and B lymphocytes, macrophages/monocytes and putative haematopoietic precursors and used them for an immunophenotyping of leukocyte subsets of peripheral blood, spleen and bone marrow samples. Overall, we found that the leukocyte composition of NMR peripheral blood is comparable to that of mice. Notably, the frequency of cytotoxic T cells was found to be lower in the NMR compared to corresponding mouse tissues and human blood. Antibodies used in the present paper are available either commercially or from the scientific community and will provide new opportunities for the NMR as a model system in ageingand cancer-related research areas.Keywords: granulocytes r haematopoietic precursors r lymphocytes r myeloid cells r naked mole rat Additional supporting information may be found online in the Supporting Information section at the end of the article. years, which is five times longer than expected based on its body size, and exhibits neither significant senescence nor an age-related increase in mortality [1]. Moreover, spontaneous carcinogenesis was observed only recently in aged animals [2,3]. Several intrinsic protective cancer-related molecular mechanisms of the NMR were reported, including activity of the INK4 locus and mutation of the ERAS oncogene [4, 5], but they were not related to the NMR immune system.

The Src-family tyrosine kinase Lck is an enzyme associated with the CD4 and CD8 co-receptors and promoting signaling through the T cell receptor (TCR) complex. The levels of Lck expression and activity change during the development and differentiation of T cells. Here we show that Lck expression is higher in Th1 cells as compared to Th2 cells. Ectopic overexpression of Lck in Th2 cells results in increased expression of CD4 co-receptor and enhanced S73 phosphorylation of transcription factor c-Jun. Our findings indicate that TCR-mediated signaling in Th2 cells may be directly attenuated by Lck protein expression level.

Tumor necrosis factor (TNF) is one of the key primary response genes in the immuneKeywords: Chromatin conformation r Th cells r T lymphocyte r TNF r Transcription start site Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTumor necrosis factor (TNF) is a pleiotropic cytokine expressed by various types of lymphoid and myeloid cells, including T cells, B cells, NK cells, monocytes, macrophages, DCs, and mast cells (reviewed in [1,2]). TNF is involved in development, homeostasis, and activation of the immune system [3][4][5][6][7][8]. Physiological functions mediated by TNF depend on the cellular sources and the molecular form of this cytokine [9][10][11]. In particular, TNF produced by macrophages and T cells plays different roles in immune and inflammatory reactions [9,10]. TNF is the primary response gene in macrophages where it has a permissive chromatin conformation [12,13]. Even without stimulation, the proximal TNF Correspondence: Dr. Yury V. Shebzukhov e-mail: shebzukhov@drfz.de promoter and transcription start site (TSS) have an open chromatin configuration in primary monocytes and macrophages and in the majority of tested myelomonocytic cell lines [14][15][16][17][18][19][20][21][22]. Various T-cell subsets produce different amounts of TNF in correlation with their pathophysiological potential [23]. Earlier studies [24] as well as recent advances in high-throughput analysis of DNaseI chromatin accessibility indicate that the proximal part of the TNF promoter in T cells is open (Supporting Information Fig. 1); however, in contrast to macrophages, the TSS of TNF in T cells acquires open chromatin conformation only after activation or polarization under Th1 or Th17 (where Th is T helper) conditions. TNF gene expression in T cells is regulated by the NFAT and AP-1 families of transcription factors; in particular, activation of the proximal TNF promoter region involves functional interactions with the transcription factors NFATc2 and c-Jun [25][26][27][28][29][30][31]. Numerous reports also supported the involvement of the NF-κB family members in transcriptional regulation of the TNF gene inwww.eji-journal.eu 252Yury V. Shebzukhov et al. Eur. J. Immunol. 2014. 44: 251-264 macrophages, in spite of the lack of canonical high-affinity NF-κB binding sites within the proximal TNF promoter [32][33][34][35][36][37][38][39]. However, specific role of NF-κB family members in regulation of the TNF gene is still being debated ([1, 2] and Discussion section). In murine T cells, members of the NF-κB family were shown to bind to the distal part of the TNF promoter [40] and to the enhancer element immediately downstream of the TNF gene (3 -TNF enhancer) [24], but the functional significance of these interactions is not clear.Here, we demonstrate the difference in chromatin structure around TNF TSS between T cells and macrophages. We further show that active forms of c-Jun and NFATc2 transcription factors are involved in chromatin remodeling oc...

This chapter provides protocols for in vitro and in vivo analysis of TNF-producing cells from a novel TNF reporter mouse. In these transgenic mice, genetic sequence encoding far-red reporter protein Katyushka (FRFPK) was placed under control of the same regulatory elements as TNF, thus providing the basis for detection, isolation, and visualization of TNF-producing cells.

No abstract

No abstract