Exposure to cigarette smoke (CS) is the predominant risk factor for the development of chronic obstructive pulmonary disease (COPD), which affects as many as 10% of individuals over the age of 40 worldwide. Although many studies have focused on the proinflammatory mechanisms of myeloid cells in COPD, evidence is accumulating for a lymphocyte-driven autoimmune component to this disease. In this issue, Eppert et al. (p. 1331) found that T cells from the lungs of mice chronically exposed to CS caused inflammatory lung pathology when transferred into immunocompentent naive mice. Analysis of these donor T cells revealed that CS exposure enhanced the production of the proinflammatory cytokines IFN-γ and TNF-α in CD8+ T cells and increased the prevalence of Th1 and Th17 phenotypes in CD4+ T cells, relative to controls. This proinflammatory skewing was not associated with changes in regulatory T cell numbers or activity, and transfer of both CD4+ and CD8+ T cells was necessary to induce lung pathology in wild-type mice. Following transfer of CS-exposed T cells, alveolar destruction, leukocytic accumulation, and inflammation did not occur in the lungs of MHC class I–deficient mice, suggesting that the transferred T cells acted in an Ag-specific manner. This study presents strong evidence for T cell–mediated autoimmunity in a mouse model of CS-induced COPD.

The specifics of how T cells recirculate from peripheral tissues have been the subject of many assumptions with little direct evidence. To provide such evidence, Bromley et al. (p. 970) have used a light-sensitive protein (Kaede) to track how cutaneous CD4+ T cells move from the skin to the lymph nodes. In the process, they identified a new memory T lymphocyte type termed recirculating memory T cells (TRCM). This migrating population had the unique phenotype of CCR7int/+CD62LintCD69CD103+/− E-selectin ligands+· These cells migrated from the skin to the draining lymph nodes in a CCR7-dependent manner, and differed from other memory T cells that reside in the tissue long term or travel between the lymph tissue and periphery. TRCM cells moved from draining lymph nodes into the circulation, then traveled to distant lymph nodes and sites of inflammation in the cutaneous tissue. TRCM cells were able to express CD40L and produce IL-2 after in vitro polyclonal stimulation. Thus, the authors have identified the novel cell type, TRCM, which differ from classical T effector memory cells in that they recirculate and use CCR7 to exit from the skin.

Immunity to Plasmodium falciparum malaria can take years to develop, and strategies to create a protective malaria vaccine remain elusive. It has been suggested that functional exhaustion of T and B cells may impair immunity to P. falciparum, and cells with phenotypes similar to the exhausted cells present during chronic viral infections have been observed in malaria infections. Illingworth et al. (p. 1038) have now compared the lymphocyte populations of Kenyan children living in a rural community with ongoing P. falciparum transmission with those of children from a similar nearby community where P. falciparum transmission ceased 5 y prior to the study. Persistent exposure to P. falciparum was associated with an increased proportion of “atypical” memory B cells, which have been proposed to be functionally exhausted, and a decreased proportion of naive B cells. CD4+ and CD8+ T cells expressing either programmed cell death-1 (PD-1) alone or both PD-1 and lymphocyte activation gene-3 (LAG-3) were also increased in association with chronic malaria exposure. These potentially exhausted PD-1+ LAG-3+ CD4+ T cells were mainly CD45RA+, and frequencies of the CD45RA+CD27+ subset of these cells negatively correlated with frequencies of activated B cells in persistently exposed children. This systematic analysis of children in a malaria-endemic area suggests that lymphocyte exhaustion is driven by P. falciparum exposure, rather than by other environmental factors, and clarifies obstacles to the development of immunity to malaria.

Granzyme H (GzmH) is a serine protease constitutively expressed in NK cells that induces cell death and protects against viral infection. Granzyme activity must be tightly controlled for proper immune homeostasis, but no physiological inhibitors have been identified for human GzmH. Here, Wang et al. (p. 1319) identified the protease inhibitor SERPINB1 as an intracellular inhibitor of GzmH. GzmH and SERPINB1 formed a covalent complex through GzmH-mediated cleavage of Phe343 in the SERPINB1 reactive center loop. This complex localized to secretory lysosomes in NK cells, and its formation resulted in strongly impaired GzmH proteolytic activity. SERPINB1 could inhibit GzmH-induced apoptosis in Jurkat cells, as well as cytoxicity mediated by lymphokine-activated killer cells. The crystal structures of a mutant form of SERPINB1 and of active GzmH were solved, and molecular modeling provided structural insights into the potential conformational changes involved in these molecules’ inhibitory interaction. Given the importance of cytotoxic mechanisms in protective immunity, this information may have broad applicability.

Cystic fibrosis (CF) results from mutations in the gene encoding the CF transmembrane receptor (CFTR) and is characterized by excessive inflammation and chronic infection of the lung with pathogens such as Pseudomonas aeruginosa. Autophagy has been found to be dysfunctional in CF but has not been directly linked to CF inflammatory pathology. In this issue, Mayer et al. (p. 1227) used network-level analysis to dissect inflammatory responses in CF cells and their possible relationship to autophagy. The authors first analyzed the activity of the anti-inflammatory peptide innate defense regulator (IDR)-1018, which selectively inhibited flagellin-induced inflammation in CF airway cell lines and PBMCs from CF patients. Network analysis of the interactions between IDR-1018–induced transcriptional responses and flagellin- and CFTR-mediated signaling pathways in CF cells showed that IDR-1018 acted via AMPK and Akt. Further examination of both CF patient cells and cell lines revealed dysregulated autophagy following flagellin treatment, which was reversed by IDR-1018 via modulation of the expression of a large number of autophagy-related genes. Specifically, IDR-1018 prevented the accumulation of autophagosomes in flagellin-treated CF cells via AMPK–Akt signaling and thereby attenuated inflammation. These data provide a mechanistic link between autophagy and lung inflammation in CF and suggest potential targets for future therapeutics aimed at limiting this inflammation.

B cell maturation involves many steps, some of which require signals and physical interaction with cell types in bone marrow microenvironments. Park et al. (p. 1094) determined that a cytoplasmic tyrosine kinase, focal adhesion kinase (FAK), was necessary for proper B cell localization within the bone marrow and was thus important for proper B cell development. B cell–specific FAK knockout mice had reduced numbers of progenitor pro-B, pre-B, and immature B cells compared with wild-type mice. In the presence of methylcellulose and IL-7 ± CXCL12, pro-B cells deficient in Fak produced fewer cells and colonies. Fak was also found to be necessary for the correct compartmentalization of pro-B cells in the bone marrow. In Fak-deficient mice, the pro-B cells were no longer found preferentially near the endosteum layer of the metaphysis and diaphysis regions of the long bone and pro-B cells were released into the periphery. Immunization with nitrophenol-conjugated chicken γ-globulin in alum (NP-CGG-alum), mimicking inflammatory stress, revealed that the effects of Fak deficiency were exacerbated under these conditions. Thus FAK is necessary for the proper maintenance of pro-B cell homeostasis and development in the bone marrow.

The adaptor protein Nck has a broadly important role in cytoskeletal organization. Following TCR stimulation, Nck is recruited via its N-terminal SH3 domain to a proline-rich sequence (PRS) in CD3ε’s cytoplasmic tail. Conflicting data have accumulated regarding the role of Nck binding to the CD3ε PRS in T cell development. To resolve this issue, Borroto et al. (p. 1103) generated a knockin mouse strain (KI-PRS) with a more conservative mutation in CD3ε than those used in previous studies. In these mice, two central prolines in the CD3ε PRS are replaced with alanine residues. Nck could not be recruited to the PRS in KI-PRS thymocytes, which, unlike those in other models, demonstrated increased degradation of CD3ζ relative to wild-type thymocytes. Both positive and negative selection (during development of both CD4+ and CD8+ T cells) were impaired in KI-PRS mice, resulting in the accumulation of thymocytes at intermediate stages of differentiation. The data suggested that CD3ε PRS was required for both pre-TCR and TCR signaling, and consequently, KI-PRS mice had a partial block at every stage of thymic differentiation requiring signaling through these receptors. Mechanistically, Nck binding to the CD3ε PRS was found to be necessary for tyrosine phosphorylation of CD3ζ and the subsequent binding and activation of ZAP70. Taken together, these data reveal a vital role for Nck interaction with the CD3ε PRS for proper T cell development.

Salmonella is an intracellular pathogen that has evolved numerous tactics to evade immune responses. Perez-Lopez et al. (p. 1201) identified a novel mechanism that Salmonella enterica uses to evade B cell responses. They found that although Salmonella infection causes IL-1β release in macrophages, this cytokine is not produced by Salmonella-infected B cells, thereby preventing IL-1β–dependent pyroptosis. Expression of the Nod-like receptor (NLR) family CARD domain containing protein 4 (NLRC4) inflammasome was reduced in infected B cells, resulting in the inhibition of normal IL-1β release. Transcription of the NLRC4 inflammasome was blocked by the action of the Salmonella pathogenicity island 1 type III secretion system. Salmonella infection of B cells caused phosphorylation of Yap, which then interacted with tyrosine protein kinase Hck to block NLRC4 transcription. Thus, Salmonella has evolved a novel system in B cells to block IL-1β secretion and cell death through downregulation of the NLRC4 inflammasome, allowing for bacterial persistence.