Even if you are not an immunologist, it does appear that way. Take for example the metabolic syndrome, a group of symptoms that includes central obesity, high blood pressure, high triglycerides, insulin resistance, and low high-density lipoprotein (HDL). The logical assumption is that insulin resistance is the primary cause and that it is primarily a metabolic disease. If one has insulin resistance, then glucose cannot enter into cells and, as a result, more and more insulin is produced. The increased levels of insulin and glucose affect kidney function and result in metabolic changes. The other change that has been described is an increase in inflammatory markers. There are adipose tissue macrophages (ATMs) that are found in fat and may contribute to insulin resistance. But which comes first? Is it the accumulation of fat that is inflammatory, or is the inflammation responsible for the insulin resistance?
In a recent issue of Nature Medicine, three articles demonstrate that the adaptive immune response, specifically T cells, actively interact with the innate immune response and contribute to the inflammatory response. These cells can modulate other inflammatory cells through development of pro-inflammatory T cells (TH1 or TH17) or more humoral responses (TH2). The paper by Winer et al. from the lab of Michael Dosch in Toronto and the other two articles1,2 demonstrate that there are changes in the CD4/ CD8 T cells before ATMs infiltrate fat. They note that in diet-induced obesity there is an expansion of TH1 (but not TH17) cells in adipose tissue that is body-mass dependent. There is also a concurrent decline in regulatory T cells (Tregs, CD4+Foxp3+). Similar findings were seen in human adipose tissue. As mice became obese, Treg numbers decreased, thus giving Tregs improved glucose tolerance through production of IL-10. They also studied Rag-1 knockout mice, which have lower numbers of lymphocytes and worse insulin resistance compared to controls. Transfer of CD4+ cells (but not CD8+) normalized glucose tolerance in these animals. The CD4+ TH2 population was the important one that led to improvement of glucose tolerance. These data suggest that the TH2 cells modulate the ATM responses. Surprisingly, these T cells have unique T-cell receptors (TCRs) that are likely to recognize specific antigens in fat tissue. The authors then probed the overall impact of T cells by using immunotherapy with anti-CD3 specific antibody or its non-mitogenic F(ab)2 fragment. Both approaches normalized insulin resistance and glucose homeostasis and selectively restored Tregs in the adipose tissue. This treatment lasted for months despite a continued high-fat diet.
In Brief
So, these results would suggest that the sequence of events that leads to obesity begins with the T cells that are fat-associated. There are Tregs that dampen inflammation from the ATMs. As they become overwhelmed by increasing insulin resistance response from fat tissue macrophages, a TH1 inflammatory response predominates leading to the metabolic syndrome. Targeting this inflammatory response has the potential to reverse the course. Of course, broad targeting of all T cells could result in systemic immune suppression. However, since there are unique T cells that are responsive to fat antigens, specific targeting of these cells could result in the resolution of the metabolic syndrome.
References
Competing Interests
Dr. Chao indicated no relevant conflicts of interest.
