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A New Partner for Invariant Chain
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Orchestrating the NKT Response
Although NKT cells are known to participate in immune responses to infection, the natural course of the NKT cell response to microbial infection has not been described. To examine this course, Chiba et al. (p. 2292 ) followed the fate of NKT cells during infection of mice with Mycobacterium bovis bacillus Calmette-Guérin. Prior to the MHC-restricted T cell response, NKT cells were activated and expanded. As the adaptive response began to take over, NKT cell proliferation waned and total NKT cell numbers declined to near baseline levels. Contraction of the NKT cell population was attributable to both increased apoptosis and reduced proliferation. Intriguingly, most of the surviving NKT cells were unresponsive to stimulation despite the continued presence of bacteria. A similar pattern of NKT cell activation followed by anergy was observed after a single injection with the TLR4 agonist LPS, suggesting that this phenomenon may occur during the course of many bacterial infections. Thus, NKT cells participate in the early phase of the antimicrobial response and then "pass the baton" to the MHC-restricted T cell response. Further, the data identify NKT cell unresponsiveness as a mechanism by which NKT cell antimicrobial responses may be terminated.
A New Type of Regulatory T Cell
Activation of the aryl hydrocarbon receptor (AhR) by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to lead to immune suppression via effects on CD4+ T cells. To determine the mechanism of this suppression, Marshall et al. (p. 2382 ) compared the characteristics of suppressive T cells generated in the presence of TCDD, referred to as TCDD-CD4+, with those of conventional regulatory T cells (Treg). Like natural Treg, TCDD-CD4+ produced very little IL-2 and suppressed proliferation and IL-2 production by responder T cells through a cell contact-dependent mechanism. Suppression could be abrogated by costimulation through glucocorticoid-induced TNFR (GITR). However, unlike natural Treg, TCDD-CD4+ did not express FoxP3 and were able to proliferate while exerting their suppressive function. TCDD-CD4+ cells produced high levels of IL-10 after stimulation with anti-CD3 or alloantigen, and microarray analysis demonstrated the up-regulation of several genes characteristic of natural Treg. Interestingly, components of the IL-12R signaling pathway were also up-regulated in TCDD-CD4+ cells, and these cells consequently showed enhanced responsiveness to IL-12. TCDD-mediated activation of the AhR therefore induces the generation of a novel subset of regulatory T cells that may be involved in the suppression of alloimmune and other immune responses in vivo.
Eosinophils Attack
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NOD2 versus TLR2
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B signaling and cytoskeletal reorganization and was previously shown to positively regulate TLR2 signaling. Eitel et al. (p. 2664
) assessed whether Rac1 might also play a role in NOD2 signaling and observed that Rac1 was activated following NOD2 stimulation. Inhibition of Rac1 increased NOD2-mediated IL-8 production and NF-B activity but decreased IL-8 production and NF-B activity that were dependent on TLR2. These data indicated that Rac1, seemingly paradoxically, inhibited NOD2 activity but promoted TLR2 activity. Experiments to determine the mechanism of Rac1-mediated NOD2 inhibition showed that Rac1 directly associated with NOD2 and induced the recruitment of this complex to the plasma membrane. β-PIX, which interacts with Rac1, was also involved in membrane recruitment of NOD2 and the inhibition of NOD2-mediated IL-8 production but did not affect TLR2-mediated IL-8 production. Finally, Rac1 activity appeared to lead to an association between NOD2 and its negative regulator Erbin. These data delineate a mechanism by which NOD2 signaling may be fine tuned and indicate that Rac1 may, through specific pathways, both promote and down-regulate inflammatory processes. HLA and HIV Transmission
Specific HLA alleles are known to affect HIV-1 pathogenesis. Over a 12-year study period, Tang et al. (p. 2626 ) analyzed 429 HIV-1 discordant Zambian couples (consisting of an HIV-infected index partner and a cohabiting seronegative partner) to determine the possible association of specific HLA haplotypes with HIV-1 transmission. These couples were divided into 205 pairs between whom viral transmission occurred and 224 who did not transmit the virus during the study period. Extensive statistical analysis of HIV-infected index partners showed that HLA class I allele A*36 was significantly associated with viral transmission, whereas the B*57 and Cw*18 alleles were negatively associated with transmission. The Cw*18 allele was also strongly associated with a low viral load, which is known to decrease the likelihood of HIV transmission, whereas A*36 tended to be associated with higher viral loads. However, the presence of the A*36, B*57, or Cw*18 alleles in the seronegative partners showed no association with viral acquisition. This complex study of a very large cohort of discordant couples identifies a strong contribution of the HLA class I genotype of the infected index partner to HIV transmission. HLA alleles therefore not only affect HIV pathogenesis, but also influence viral transmission.
A Broken Heart without PD-L1
The PD-1/PD-L1 costimulatory pathway suppresses autoimmune kidney disease, leading Lucas et al. (p. 2513 ) to hypothesize that this pathway might also inhibit the spontaneous macrophage and T cell-dependent, lupus-like disease that develops in MRL-Faslpr mice. They therefore generated mice deficient in PD-L1 on the MRL-Faslpr background. Unexpectedly, these PD-L1–/–; MRL-Faslpr mice did not develop kidney disease but instead demonstrated severe myocarditis and pneumonitis and died much earlier than their wild-type (WT); MRL-Faslpr littermates. This disease was characterized by a massive infiltration of PD-1-expressing macrophages and T cells into the heart and lung. Following disease onset, high levels of autoantibodies specific for cardiac myosin and troponin I were detected in PD-L1–/–; MRL-Faslpr mice but not WT; MRL-Faslpr mice. This autoimmune pathology was dependent upon the MRL background but not the Faslpr mutation. Interestingly, transfer of PD-L1–/–; MRL+/+ bone marrow into WT; MRL+/+ mice was sufficient to induce myocarditis and pneumonitis in the recipient mice, albeit to a less severe degree than that seen in PD-L1–/–;MRL+/+ mice. This decrease in disease severity was associated with a dramatic up-regulation of PD-L1 in the heart and lung endothelial cells. The analysis of disease in this model provides novel insights into the autoimmune susceptibility of MRL mice and potential roles of the PD-1/PD-L1 pathway in protection against autoimmune inflammation.
Electric Attraction
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Summaries written by Jennifer Hartt Meyers, Ph.D.
Related articles in The JI:
Receptor and Modulates Its Trafficking to Endosomal/Lysosomal Compartments
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