T helper 17 (T(H)17) cells and interleukin-17A (IL-17A) produced by them are critical in autoinflammatory diseases, such as psoriasis. IL-17A has been shown to signal through IL-17 receptor A/IL-17 receptor C (IL-17RA/IL-17RC) complex to drive inflammatory responses. However, in a psoriasis model, we found that Il17rc deficiency did not completely ameliorate the disease, suggesting another receptor. In search for another IL-17A-interacting receptor, we found that IL-17RD directly bound IL-17A but not IL-17F or IL-17A/F heterodimer and formed a heterodimer with IL-17RA. IL-17A-, but not IL-17F- or IL-17A/F-, mediated gene expression was defective in Il17rd-deficient keratinocytes. Il17rd deficiency in nonhemopoietic cells attenuated imiquimod-induced psoriasis-like skin inflammation. Although IL-17RC and IL-17RD differentially activated IL-17A-dependent signaling and gene expression, their compound mutation led to complete deficits in keratinocytes. IL-23 was found induced by IL-17A in keratinocytes, dependent on both IL-17RC and IL-17RD, suggesting feed-forward regulation of IL-23/IL-17 axis in psoriasis. Together, IL-17RD constitutes a second functional receptor for IL-17A and, together with IL-17RC, mediates the proinflammatory gene expression downstream of IL-17A.
The cause of most hypertensive disease is unclear, but inflammation appears critical in disease progression. However, how elevated blood pressure initiates inflammation is unknown, as are the effects of high blood pressure on innate and adaptive immune responses. We now report that hypertensive mice have increased T cell responses to antigenic challenge and develop more severe T cell-mediated immunopathology. A root cause for this is hypertension-induced erythrocyte adenosine 5'-triphosphate (ATP) release, leading to an increase in plasma ATP levels, which begins soon after the onset of hypertension and stimulates P2X7 receptors on antigen-presenting cells (APCs), increasing APC expression of CD86. Hydrolyzing ATP or blocking the P2X7 receptor eliminated hypertension-induced T cell hyperactivation. In addition, pharmacologic or genetic blockade of P2X7 receptor activity suppressed the progression of hypertension. Consistent with the results in mice, we also found that untreated human hypertensive patients have significantly elevated plasma ATP levels compared with treated hypertensive patients or normotensive controls. Thus, a hypertension-induced increase in extracellular ATP triggers augmented APC and T cell function and contributes to the immune-mediated pathologic changes associated with hypertensive disease.
CD8(+) tissue-resident memory T (T-RM) cells provide frontline immunity in mucosal tissues. The mechanisms regulating CD8(+) T-RM maintenance, heterogeneity, and protective and pathological functions are largely elusive. Here, we identify a population of CD8(+) T-RM cells that is maintained by major histocompatibility complex class I (MHC-I) signaling, and CD80 and CD86 costimulation after acute influenza infection. These T-RM cells have both exhausted-like phenotypes and memory features and provide heterologous immunity against secondary infection. PD-L1 blockade after the resolution of primary infection promotes the rejuvenation of these exhausted-like T-RM cells, restoring protective immunity at the cost of promoting postinfection inflammatory and fibrotic sequelae. Thus, PD-1 serves to limit the pathogenic capacity of exhausted-like T-RM cells at the memory phase. Our data indicate that T-RM cell exhaustion is the result of a tissue-specific cellular adaptation that balances fibrotic sequelae with protective immunity.
Immunological tolerance of tumors is characterized by insufficient infiltration of cytotoxic T lymphocytes (CTLs) and immunosuppressive microenvironment of tumor. Tumor resistance to immune checkpoint inhibitors due to immunological tolerance is an ongoing challenge for current immune checkpoint blockade (ICB) therapy. Here, we report the development of tumor microenvironment-activatable anti-PDL1 antibody (alpha PDL1) nanoparticles for combination immunotherapy designed to overcome immunological tolerance of tumors. Combination of alpha PDL1 nanoparticle treatment with near-infrared (NIR) laser irradiation-triggered activation of photosensitizer indocyanine green induces the generation of reactive oxygen species, which promotes the intratumoral infiltration of CTLs and sensitizes the tumors to PDL1 blockade therapy. We showed that the combination of antibody nanoparticles and NIR laser irradiation effectively suppressed tumor growth and metastasis to the lung and lymph nodes in mouse models. The nanoplatform that uses the antibody nanoparticle alone both for immune stimulation and PDL1 inhibition could be readily adapted to other immune checkpoint inhibitors for improved ICB therapy.
IL-6 inhibits the expression of IL-2R beta (CD122) in germinal center T-FH cells to maintain IL-2 hyporesponsiveness (see the related Research Article by Papillion et al.).