Traditional wisdom holds that intact immune responses, such as immune surveillance or immunoediting, are required for preventing and inhibiting tumor development; but recent evidence has also indicated that unresolved immune responses, such as chronic inflammation, can promote the growth and progression of cancer. Within the immune system, cytotoxic CD8+ and CD4+ Th1 T cells, along with their characteristically produced cytokine IFN-γ, function as the major anti-tumor immune effector cells, whereas tumor associated macrophages (TAM) or myeloid-derived suppressive cells (MDSC) and their derived cytokines IL-6, TNF, IL-1β and IL-23 are generally recognized as dominant tumor-promoting forces. However, the roles played by Th17 cells, CD4+ CD25+ Foxp3+ regulatory T lymphocytes and immunoregulatory cytokines such as TGF-β in tumor development and survival remain elusive. These immune cells and the cellular factors produced from them, including both immunosuppressive and inflammatory cytokines, play dual roles in promoting or discouraging cancer development, and their ultimate role in cancer progression may rely heavily on the tumor microenvironment and the events leading to initial propagation of carcinogenesis.

Obesity is associated with an activated macrophage phenotype in multiple tissues that contributes to tissue inflammation and metabolic disease. To evaluate the mechanisms by which obesity potentiates myeloid activation, we evaluated the hypothesis that obesity activates myeloid cell production from bone marrow progenitors to potentiate inflammatory responses in metabolic tissues. High fat diet-induced obesity generated both quantitative increases in myeloid progenitors as well as a potentiation of inflammation in macrophages derived from these progenitors. In vivo, hematopoietic stem cells from obese mice demonstrated the sustained capacity to preferentially generate inflammatory CD11c+ adipose tissue macrophages after serial bone marrow transplantation. We identified that hematopoietic MyD88 was important for the accumulation of CD11c+ adipose tissue macrophage accumulation by regulating the generation of myeloid progenitors from HSCs. These findings demonstrate that obesity and metabolic signals potentiate leukocyte production and that dietary priming of hematopoietic progenitors contributes to adipose tissue inflammation.

Objective The relationship between adipose tissue fibrosis, adipocyte hypertrophy, and preadipocyte hyperplasia in the context of obesity, and the correlation of these tissue-based phenomena with systemic metabolic disease are poorly defined. The goal of this study was to define clarify the relationship between adipose tissue fibrosis, adipocyte hypertrophy, and preadipocyte hyperplasia in human obesity and determine the correlation of these adipose-tissue based phenomena with diabetes. Methods Visceral and subcutaneous adipose tissues from humans with obesity collected during bariatric surgery were studied with QRTPCR, immunohistochemistry, and flow cytometry for expression of collagens and fibrosis-related proteins, adipocyte size, and preadipocyte frequency. Results were correlated with clinical characteristics including diabetes status. Results Fibrosis was decreased, hypertrophy was increased, and preadipocyte frequency and fibrotic gene expression were decreased in adipose tissues from diabetic subjects compared to non-diabetic subjects. These differences were greater in visceral compared to subcutaneous adipose tissue. Conclusions These data are consistent with the hypothesis that adipose tissue fibrosis in the context of human obesity limits adipocyte hypertrophy and is associated with a reciprocal increase in adipocyte hyperplasia, with beneficial effects on systemic metabolism. These findings suggest adipose tissue fibrosis as a potential target for manipulation of adipocyte metabolism.

Summary An adaptive immune response triggered by obesity is characterized by the activation of adipose tissue CD4+ T cells by unclear mechanisms. We have examined if interactions between adipose tissue macrophages (ATMs) and CD4+ T cells contribute to adipose tissue metainflammation. Intravital microscopy identifies dynamic antigen dependent interactions between ATMs and T cells in visceral fat. Mice deficient in major histocompatibility complex class II (MHCII) showed protection from diet-induced obesity. Deletion of MHCII expression in macrophages led to an adipose tissue specific decrease in the effector/memory CD4+ T cells, attenuation of CD11c+ ATM accumulation, and improvement in glucose intolerance by increasing adipose tissue insulin sensitivity. Ablation experiments demonstrated that the maintenance of proliferating conventional T cells is dependent on signals from CD11c+ ATMs in obese mice. These studies demonstrate the importance of MHC Class II restricted signals from ATMs that regulate adipose tissue T cell maturation and metainflammation.

Dynamic changes of adipose tissue leukocytes, including adipose tissue macrophage (ATM) and adipose tissue dendritic cells (ATDC) contribute to obesity-induced inflammation and metabolic disease. However, clear discrimination between ATDC and ATM in adipose tissue has limited progress in the field of immunometabolism. In this study, we utilize CD64 to distinguish ATM and ATDC and investigated the temporal and functional changes in these myeloid populations during obesity. Flow cytometry and immunostaining demonstrated that the definition of ATM as F4/80+CD11b+ cells overlaps with other leukocytes and that CD45+CD64+ is specific for ATM. The expression of core DC genes were enriched in CD11c+CD64− cells (ATDC), while core macrophage genes were enriched in CD45+CD64+ cells (ATM). CD11c+CD64− ATDC expressed MHCII and co-stimulatory receptors and had similar capacity to stimulate CD4+ T cell proliferation as ATM. ATDC were predominantly CD11b+ conventional DCs and made up the bulk of CD11c+ cells in adipose tissue with moderate high fat diet exposure. Mixed chimeric experiments with Ccr2−/− mice demonstrated that high-fat diet (HFD) induced ATM accumulation from monocytes was dependent on CCR2; while ATDC accumulation was less CCR2-dependent. ATDC accumulation during obesity was attenuated in Ccr7−/− mice and was associated with decreased adipose tissue inflammation and insulin resistance. CD45+CD64+ ATM and CD45+CD64−CD11c+ ATDC were identified in human obese adipose tissue and ATDC were increased in subcutaneous adipose tissue compared to omental. These results support a revised strategy for unambiguous delineation of ATM and ATDC and suggests that ATDC are independent contributors to adipose tissue inflammation during obesity.