The role of Killer T cells in adipose tissue inflammation

A number of good posts have gone up in recent weeks detailing the now well established connection between systematic insulin resistance and a state of chronic low grade inflammation in adipose tissue. ElhamV495K and Randy Taylor explore in more detail the vast web of cytokine and chemokine interactions involved between adipose tissue and the invasive macrophages (predominantly M1) that accompany (cause?) this chronic inflammation; both do a good job, as well, of highlighting the difficulty of unraveling the cause and effect nature of this incredibly complex system.

In light of our lecture today on T cell development, I thought I'd add another piece to the puzzle: the role of CD3+CD8+CD4- cells (otherwise known as Killer T cells or CTL) in the development of obesity related adipose tissue inflammation and insulin resistance.

In both diet induced obese mice (DIO) and the leptin deficient ob/ob mice, the adipose tissue stromal vascular fraction has much higher levels of both macrophages and CTLs, and much lower levels of Helper T cells (defined by being CD3+CD4+CD8-). Furthermore, the increase in CTLs can be seen as early as 6 weeks on a high fat diet, while the increase in macrophages lags, not differing from control mice until 10 weeks. The presence of CTLs actually turns out to be necessary for initiation and maintence of macrophage recruitment: by regularly injecting mice with a CD8 antibody, the majority of M1 macrophage infiltration and many of the metabolic effects of DIO can be prevented (in young mice) or ameliorated (in mice with already established cronic inflammation).

Prior to reading this finding, the chronic inflammation associated with DIO looked, to me, very much like the innate immune response we learned about in our first class: damaged peripheral tissue releasing cytokines and chemokines, recruiting phagocytic white blood cells. However, this finding shows that the inflammation is actually directly tied to and reliant on the adaptive immune response. While the infiltrating CTLs are not monoclonal, as might be expected in a traditional "vs. self" autoimmune response, they do have preferential expression of two variable region receptor minigenes, suggesting that they are being activated by some epitope or family of epitopes in the adipose tissue (neither CTLs or adipose tissue alone will recruit macrophages, but lean adipose tissue combined with these CTLs is sufficient for M1 recruitment and activation).

Hopefully, this addition of another cell type to the already complicated of story of adipose tissue inflammation will help to unravel the series of events linking obesity to metabolic disease.

Reference:
CD8⁺ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity, Nature Medicine 15, 914 - 920 (2009)