Human antimicrobial cytotoxic T lymphocytes, defined by NK receptors and antimicrobial proteins, kill intracellular bacteria.

Human CD8+ cytotoxic T lymphocytes (CTLs) contribute to antimicrobial defense against intracellular pathogens through secretion of cytotoxic granule proteins granzyme B, perforin, and granulysin. However, CTLs are heterogeneous in the expression of these proteins, and the subset(s) responsible for antimicrobial activity is unclear. Studying human leprosy, we found that the subset of CTLs coexpressing all three cytotoxic molecules is increased in the resistant form of the disease, can be expanded by interleukin-15 (IL-15), and is differentiated from naïve CD8+ T cells by Langerhans cells. RNA sequencing analysis identified that these CTLs express a gene signature that includes an array of surface receptors typically expressed by natural killer (NK) cells. We determined that CD8+ CTLs expressing granzyme B, perforin, and granulysin, as well as the activating NK receptor NKG2C, represent a population of "antimicrobial CTLs" (amCTLs) capable of T cell receptor (TCR)-dependent and TCR-independent release of cytotoxic granule proteins that mediate antimicrobial activity.

Aquaporin-1 Expression in Herniated Human Lumbar Intervertebral Discs.

STUDY DESIGN: Case series. OBJECTIVE: Intervertebral disc (IVD) degeneration is the cause of spondylosis. The pathogenesis is poorly understood, but disc dehydration often plays a role. In this study, we aim to identify and quantify aquaporin-1 (AQP1) in ex vivo human degenerated IVDs obtained intraoperatively and to investigate the relationship between AQP1 levels and magnetic resonance imaging (MRI) T2 intensity of the disc. METHODS: Ex vivo samples of nucleus pulposus (NP) tissue from lumbar IVDs were obtained from 18 consecutive patients who underwent surgery for disc herniation at L4/5 and L5/S1 level. Immunohistochemistry was performed to determine the presence of AQP1 expression, and this was quantified by Western blot analysis. AQP1 expression was compared to preoperative IVD signal intensity on T2-weighted MRI. RESULTS: NP tissue was obtained from 18 patients (9 for L4/5 level and 9 for L5/S1 level). AQP1 expression was detected in all samples by Western blot and immunohistochemistry. AQP1 expression had a linear correlation with the preoperative IVD signal intensity on T2-weighted MRI at L4/5 level (R2 = 0.90) and at L5/S1 level (R2 = 0.92). AQP1 expression was 52.2 ± 59.0 at L5/S1 level and 15.9 ± 20.6 at L4/5 (P = .10). CONCLUSIONS: Our results show that AQP1 can be detected in IVD obtained from live human subjects. Increased AQP1 expression is associated with greater disc hydration as measured by signal intensity on T2-weighted MRI. AQP1 may have a role in the dehydration associated with disc degeneration.

Human NOD2 Recognizes Structurally Unique Muramyl Dipeptides from Mycobacterium leprae.

The innate immune system recognizes microbial pathogens via pattern recognition receptors. One such receptor, NOD2, via recognition of muramyl dipeptide (MDP), triggers a distinct network of innate immune responses, including the production of interleukin-32 (IL-32), which leads to the differentiation of monocytes into dendritic cells (DC). NOD2 has been implicated in the pathogenesis of human leprosy, yet it is not clear whether Mycobacterium leprae, which has a distinct MDP structure, can activate this pathway. We investigated the effect of MDP structure on the innate immune response, finding that infection of monocytes with M. leprae induces IL-32 and DC differentiation in a NOD2-dependent manner. The presence of the proximal l-Ala instead of Gly in the common configuration of the peptide side chain of M. leprae did not affect recognition by NOD2 or cytokine production. Furthermore, amidation of the d-Glu residue did not alter NOD2 activation. These data provide experimental evidence that NOD2 recognizes naturally occurring structural variants of MDP.