1: Obesity accelerates T-cell senescence in visceral adipose tissue.

J Clin Invest.

2016 Nov 7. pii: 88606. doi: 10.1172/JCI88606.

Shirakawa K, Yan X, Shinmura K, Endo J, Kataoka M, Katsumata Y, Yamamoto T, Anzai A, Isobe S, Yoshida N, Itoh H, Manabe I, Sekai M, Hamazaki Y, Fukuda K, Minato N, Sano M.

Kimiaki Shirakawa, Motoaki Sano (Department of Cardiology), and their colleagues, in a joint study with Professor Nagahiro Minato and others from the Department of Immunology and Cell Biology at Kyoto University, discovered in mice that a special population of CD4-positive T-cells that highly express PD-1 (Programmed cell death 1) on their cell surface

is involved in the mechanism by which chronic inflammation, originating in visceral adipose tissue due to obesity, spreads throughout the body and causes diabetes. This T-cell population appears specifically in obese mice within the visceral adipose tissue in a B-cell-dependent manner. While their ability to proliferate in response to antigen stimulation and their normal cytokine secretion capacity are reduced, they exhibit characteristics of cellular senescence, such as senescence-

associated ß-galactosidase activity. Unaffected by inhibitory signals via PD-1, they produce large amounts of osteopontin, acting as a trigger for chronic inflammation in visceral adipose tissue. It was found that this T-cell population has traits very similar to "senescence-associated T-cells," which are responsible for immunosenescence (decline in acquired immunity and chronic inflammatory state) in aged mice. Aging and visceral fat

obesity are major factors that hinder healthy longevity, being closely related not only to lifestyle-related diseases such as diabetes, myocardial infarction, and stroke, but also to the onset of susceptibility to infection, cancer, and autoimmune diseases. It is hoped that treatments controlling immunosenescence may lead to the prevention and treatment of various diseases that develop based on aging and visceral fat obesity.

(Motoaki Sano, Class of '71, and Kimiaki Shirakawa, Class of '88, Department of Cardiology)

PNAS

113 (41):E6153-E6161; 10.1073/pnas.1607787113 OCT 11 2016

Kamei Akinobu*, Gao Geli, Neale Geoffrey, Loh Lip Nam, Vogel Peter, Thomas Paul G., Tuomanen Elaine I., Murray Peter J.*

When bone marrow function is suppressed by chemotherapy, immune cells such as neutrophils decrease, increasing the host's risk of infection. It has recently become clear that some macrophages, a type of white blood cell resident in tissues, appear during the embryonic stage and are subsequently maintained autonomously within the tissue without relying on the bone marrow. We hypothesized that by remodeling the immunological environment of the lungs, particularly the tissue-resident macrophages, we could compensate for the decline in host immunity associated with myelosuppression, and we tested this hypothesis in an animal model. By administering a vaccine to mice via the airway, we were able to induce anti-Pseudomonas aeruginosa immunity that is independent of neutrophils and monocytes, with lung macrophages, assisted by T lymphocytes, as the main effectors. Furthermore, in the lungs after vaccine administration, we found a group of macrophages (ViM) with different characteristics from alveolar macrophages (AM), which are maintained by local cell division. While gene expression and other factors suggest that ViM are derived from AM, it was also found that, unlike AM, they do not decrease with anticancer drug administration and possess superior antibacterial activity. In the future, by elucidating in detail the mechanism by which ViM are induced and maintained, we hope to lead to new strategies to protect myelosuppressed patients from severe infections.

(Akinobu Kamei, Class of '79, Pediatrics, St. Jude Children's Research Hospital)