Normalization of obesity-associated insulin resistance through immunotherapy

Abstract

Progressive obesity and its associated metabolic syndromes represent a globally growing challenge, yet mechanistic understanding and current therapeutics are unsatisfactory. We discovered that CD4+ T-lymphocytes, resident in visceral adipose tissue (VAT), control insulin-resistance in diet-induced obese (DIO) mice and likely humans. DIO VAT-associated T cells display biased TCR-Vα repertoires suggesting antigen-specific expansion. CD4+ T-lymphocyte control of glucose homeostasis is compromised in DIO when VAT accumulates pathogenic IFNγ-secreting Th1 cells, overwhelming static numbers of Th2 (CD4+GATA-3+) and regulatory Foxp3+ T cells. CD4+ T cell transfer into DIO, lymphocyte-free RAGnull mice reversed weight gain and insulin resistance predominately through Th2 cells. Brief systemic treatment with αCD3 antibody or its F(ab′)2 fragment, restores the Th1/Foxp3+ balance and reverses insulin resistance for months, despite continuing high-fat diet. The progression of obesity-associated metabolic abnormalities is physiologically under CD4+ T cell control, with expansion of adipose tissue-resident T cells that can be manipulated by immunotherapy.

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

“…Infiltrating lymphocytes precede macrophage populations in obese adipose tissue concomitant with early insulin resistance and may play a role in adipose tissue inflammation by modifying the number and the activation state of adipose tissue macrophages [37][38][39][40]. In mouse models of obesity, an increased numbers of cytotoxic CD8+ effector cells is suspected to initiate the recruitment and activation of adipose tissue macrophages and promote pro-inflammatory cascades associated with insulin resistance [38,40].…”

“…In mouse models of obesity, an increased numbers of cytotoxic CD8+ effector cells is suspected to initiate the recruitment and activation of adipose tissue macrophages and promote pro-inflammatory cascades associated with insulin resistance [38,40]. Obesity also induces modification in the balance between pro-inflammatory (T helper 1 and T helper 17 lymphocytes) and antiinflammatory (T helper 2 and regulatory T lymphocytes) CD4+ cells subsets, leading to secretion of cytokines from newly recruited adipose tissue macrophages [39][40][41]. Of particular interest, the number of anti-inflammatory regulatory T lymphocytes decreases with obesity in adipose tissue of both mice and humans [37,39,40] and even more in obese patients with metabolic syndrome [33].…”

“…Obesity also induces modification in the balance between pro-inflammatory (T helper 1 and T helper 17 lymphocytes) and antiinflammatory (T helper 2 and regulatory T lymphocytes) CD4+ cells subsets, leading to secretion of cytokines from newly recruited adipose tissue macrophages [39][40][41]. Of particular interest, the number of anti-inflammatory regulatory T lymphocytes decreases with obesity in adipose tissue of both mice and humans [37,39,40] and even more in obese patients with metabolic syndrome [33]. The regulatory T lymphocytes express high amount of the antiinflammatory cytokine IL-10 which inhibit macrophage migration and induce the differentiation of M2 macrophages [35,37].…”

Le tissu adipeux

“…Des études cinétiques dans le modèle DIO révèlent que les lymphocytes T précèdent les macrophages dans le tissu adipeux [12,13]. De plus, les lymphocytes T CD4 + isolés du tissu adipeux de souris DIO expriment un répertoire TCR restreint, suggérant qu'ils puissent reconnaître un -ou des -antigènes d'origine adipeuse [14]. On distingue plusieurs profils de mobilisation des lymphocytes T dans le tissu adipeux dans l'obésité : le nombre de lymphocytes T cytotoxiques (CD8 + ) augmente alors que celui des lymphocytes T anti-inflammatoires Th2 (CD4 + GATA3 + ) et Treg (Foxp3 + ) diminue [13][14][15].…”

“…De plus, les lymphocytes T CD4 + isolés du tissu adipeux de souris DIO expriment un répertoire TCR restreint, suggérant qu'ils puissent reconnaître un -ou des -antigènes d'origine adipeuse [14]. On distingue plusieurs profils de mobilisation des lymphocytes T dans le tissu adipeux dans l'obésité : le nombre de lymphocytes T cytotoxiques (CD8 + ) augmente alors que celui des lymphocytes T anti-inflammatoires Th2 (CD4 + GATA3 + ) et Treg (Foxp3 + ) diminue [13][14][15]. L'importance physiopathologique de ces changements est illustrée par le fait que l'inactivation des T CD8 + [13] ou l'induction des lymphocytes Th2 ou des Treg [14,15] diminue l'inflammation dans le tissu adipeux des souris DIO.…”