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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased morbidity and mortality in solid organ transplant (SOT) recipients. Despite exclusion from SARS-CoV-2 vaccine clinical trials, these individuals were identified as high-risk and prioritized for vaccination in public health guidelines.We prospectively evaluated humoral and cellular immune responses to two doses of the SARS-CoV-2 mRNA vaccine, BNT162b2, in 56 SOT recipients and 26 healthy controls (HCs). Blood specimens collected from participants prior to each dose and following the second dose were tested for SARS-CoV-2-specific antibodies, as well as CD4+ and CD8+ T-cell responses.SOT recipients demonstrated lower mean anti-SARS-CoV-2 antibody levels compared to HCs after each dose, and only 21.6% achieved an antibody response after the second dose within the range of HC responses. Similarly, the percentage of responsive CD4+ and CD8+ T cells in SOT recipients was lower than in HCs. While most HCs showed notable humoral and cellular responses, responses were less concordant in SOT recipients, with some showing evidence of either humoral or cellular response, but not both.Humoral and cellular immune responses to the BNT162b2 vaccine are markedly reduced in SOT recipients as compared to HCs, suggesting that SOT recipients may benefit from more tailored regimens such as higher dose and/or additional vaccinations.

Adipose tissue contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that decrease inflammation in obese animals, but their effect on inflammation in humans is unknown. The enzyme soluble epoxide hydrolase (sEH) hydrolyzes EETs to less active diols, and we hypothesized that pharmacologic sEH inhibition would decrease adipose inflammation in obese individuals. We treated obese prediabetic adults with the sEH inhibitor GSK2256294 versus placebo in a crossover design, collected subcutaneous abdominal adipose tissue via lipoaspiration and characterized the tissue T cell profile. Treatment with GSK2256294 decreased the percentage of pro-inflammatory T cells producing interferon-gamma (IFNγ), but not interleukin (IL)-17A, and decreased the amount of secreted tumor necrosis factor-alpha (TNFα). Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate adipose and systemic inflammation.

Background: Obesity is associated with increased prevalence of type 2 diabetes and cardiovascular disease (CVD). Adipose tissue (AT) contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons. Increased chronic inflammation in obesity contributes to metabolic disease by increasing insulin resistance, and to CVD by causing an atherogenic dyslipidemia and increasing endothelial cell dysfunction and activation. Despite these links between inflammation and cardiometabolic disease in obesity, there are no current targeted therapies to prevent or reverse chronic inflammation in AT. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that act as potent vasodilators and promote sodium excretion in the kidney. Increasing EETs in rodents protects against hypertension and endothelial dysfunction. In humans, circulating EETs correlate with insulin sensitivity and are decreased in individuals with insulin resistance. EETs also decrease the inflammatory response to obesity in animal models, but the effect of EETs on inflammation in humans is currently unknown. EETs are hydrolyzed to less active forms by the enzyme soluble epoxide hydrolase (sEH), and we hypothesized that pharmacologic sEH inhibition with a specific inhibitor GSK2256294 (GSK) in obese patients would decrease AT inflammation. Methods: Thirty-four obese prediabetic individuals were treated with placebo and GSK in a crossover design (NCT03486223). Participants had a seven-week washout in between drugs, and the order of drug was randomized and blinded. In a subgroup of patients, we collected subcutaneous AT by liposuction and characterized T cell phenotypes by flow cytometry (N=7 paired samples). Results: GSK decreased sEH activity in plasma (47.3% vs placebo; P=0.008) and in AT (58.8% vs placebo; P=0.002). GSK also decreased serum F2-isoprostanes (P=0.03), which are markers of oxidative damage and inflammation. In seven paired AT samples, T helper (Th) 1 cells producing the pro-inflammatory cytokine IFNγ were reduced by treatment with GSK as compared with placebo (% of total lymphocytes: Placebo 13.6% ± 6.9, GSK 11.0% ± 5.6, P=0.03 Wilcoxon Signed Rank). In this small sample, we did not detect significant differences in the percentage of other IFNγ-producing cells (natural killer: Placebo 19.0% ± 9.0, GSK 13.3% ± 4.9, P=0.18; CD8: Placebo 12.0 ± 11.0, GSK 6.1 ± 4.6, P=0.61). In addition, we did not detect any change in Th17, Th2, or regulatory T cells. Conclusions: In a pilot study of seven individuals treated with placebo or an sEH inhibitor, we found that the sEH inhibitor decreased pro-inflammatory Th1 cells as compared with placebo in matched AT samples. Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate AT and systemic inflammation and reduce the risk of CVD.

Summary Persons with HIV are at increased risk for diabetes mellitus compared with individuals without HIV. Adipose tissue is an important regulator of glucose and lipid metabolism, and adipose tissue T cells modulate local inflammatory responses and, by extension, adipocyte function. Persons with HIV and diabetes have a high proportion of CX3CR1+ GPR56+ CD57+ (C-G-C+) CD4+ T cells in adipose tissue, a subset of which are cytomegalovirus specific, whereas individuals with diabetes but without HIV have predominantly CD69+ CD4+ T cells. Adipose tissue CD69+ and C-G-C+ CD4+ T cell subsets demonstrate higher receptor clonality compared with the same cells in blood, potentially reflecting antigen-driven expansion, but C-G-C+ CD4+ T cells have a more inflammatory and cytotoxic RNA transcriptome. Future studies will explore whether viral antigens have a role in recruitment and proliferation of pro-inflammatory C-G-C+ CD4+ T cells in adipose tissue of persons with HIV., Graphical Abstract, Highlights Adipose tissue memory CD4+ T cells are frequently CD69+ in persons with diabetes Persons with HIV and diabetes have more CX3CR1+ GPR56+ CD57+ (C-G-C+) CD4+ T cells Adipose tissue C-G-C+ CD4+ T cells and CD69+ CD4+ T cells are clonally expanded C-G-C+ CD4+ T cells are often CMV specific and have more inflammatory transcriptomes, Wanjalla et al. demonstrate that adipose tissue in persons with HIV and diabetes includes a large proportion of clonally expanded, inflammatory, and frequently CMV-specific CX3CR1+ GPR56+ CD57+ (C-G-C+) CD4+ T cells. These cells may contribute to the altered adipocyte function and elevated risk of metabolic disease observed among persons with HIV.

Chronic T cell activation and accelerated immune senescence are hallmarks of HIV infection, which may contribute to the increased risk of cardiometabolic diseases in people living with HIV (PLWH). T lymphocytes play a central role in modulating adipose tissue inflammation and, by extension, adipocyte energy storage and release. Here, we assessed the CD4+ and CD8+ T cell profiles in the subcutaneous adipose tissue (SAT) and blood of non-diabetic (n = 9; fasting blood glucose [FBG] < 100 mg/dL), pre-diabetic (n = 8; FBG = 100–125 mg/dL) and diabetic (n = 9; FBG ≥ 126 mg/dL) PLWH, in addition to non- and pre-diabetic, HIV-negative controls (n = 8). SAT was collected by liposuction and T cells were extracted by collagenase digestion. The proportion of naïve (TNai) CD45RO−CCR7+, effector memory (TEM) CD45RO+CCR7−, central memory (TCM) CD45RO+CCR7+, and effector memory revertant RA+(TEMRA) CD45RO−CCR7− CD4+ and CD8+ T cells were measured by flow cytometry. CD4+ and CD8+ TEM and TEMRA were significantly enriched in SAT of PLWH compared to blood. The proportions of SAT CD4+ and CD8+ memory subsets were similar across metabolic status categories in the PLWH, but CD4+ T cell expression of the CD69 early-activation and tissue residence marker, particularly on TEM cells, increased with progressive glucose intolerance. Use of t-distributed Stochastic Neighbor Embedding (t-SNE) identified a separate group of predominantly CD69lo TEM and TEMRA cells co-expressing CD57, CX3CR1, and GPR56, which were significantly greater in diabetics compared to non-diabetics. Expression of the CX3CR1 and GPR56 markers indicate these TEM and TEMRA cells may have anti-viral specificity. Compared to HIV-negative controls, SAT from PLWH had an increased CD8:CD4 ratio, but the distribution of CD4+ and CD8+ memory subsets was similar irrespective of HIV status. Finally, whole adipose tissue from PLWH had significantly higher expression of TLR2, TLR8, and multiple chemokines potentially relevant to immune cell homing compared to HIV-negative controls with similar glucose tolerance.