Premature CD4+ T Cell Aging and Its Contribution to Lymphopenia-Induced Proliferation of Memory Cells in Autoimmune-Prone Non-Obese Diabetic Mice

Ting-Ting Sheu,Jui-Hung Yen,Bor-Luen Chiang,Wen-Chi Lin,Lucienne Chatenoud

doi:10.1371/journal.pone.0089379

Ting-Ting Sheu, Jui-Hung Yen + Show 3 more

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https://doi.org/10.1371/journal.pone.0089379

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Abstract

Lymphopenia-induced proliferation (LIP), a mechanism to maintain a constant number of T cells in circulation, occurs in both normal aging and autoimmune disease. The incidence of most autoimmune diseases increases with age, and premature CD4+ T cell aging has been reported in several autoimmune diseases. In this study, we tested the hypothesis that premature CD4+ T cell aging can cause autoimmune disease by examining whether premature CD4+ T cell aging exists and causes LIP in our mouse model. Non-obese diabetic (NOD) mice were used because, in addition to Treg defects, the LIP of T cells has been shown to plays a causative role in the development of insulin-dependent diabetes mellitus (IDDM) in these mice. We found that with advancing age, NOD mice exhibited an accelerated decrease in the number of CD4+ T cells due to the loss of naïve cells. This was accompanied by an increase in the percentage of memory cells, leading to a reduced naïve/memory ratio. In addition, both the percentage of CD28+ cells in CD4+ T cells and IL-2 production decreased, while the percentage of FAS+CD44+ increased, suggesting that NOD mice exhibit premature CD4+ T cell aging. This process preferentially contributed to LIP of memory cells. Therefore, our results suggest that premature CD4+ T cell aging underlies the development of IDDM in NOD mice. Given that CD28 and IL-2 play important roles in Treg function, the relationships between premature CD4+ T cell aging and lymphopenia as well as Treg defects in autoimmune-prone NOD mice are proposed.

Highlights

In lymphopenia, when the number of circulating lymphocytes is reduced due to recent infection, leukemia, or treatment with certain cytotoxic medications, an autoproliferation mechanism known as lymphopenia-induced proliferation (LIP) works to maintain the T cell number at a constant level
Our results demonstrate the presence of premature CD4+ T cell aging and its preferential contribution to LIP of memory cells in autoimmune disease-prone non-obese diabetic (NOD) mice, and suggest that premature CD4+ T cell aging underlies the development of autoimmunity
Because reduced CD4+ T cell number is a characteristic of immune aging, these results suggest that NOD mice undergo a process of premature immune aging or at least premature T cell aging

Summary

Introduction

In lymphopenia, when the number of circulating lymphocytes is reduced due to recent infection, leukemia, or treatment with certain cytotoxic medications, an autoproliferation mechanism known as lymphopenia-induced proliferation (LIP) works to maintain the T cell number at a constant level. With aging, reduced thymic output of naıve T cells will trigger LIP to maintain homeostasis in humans [1]. In addition to normal physiological situations, LIP can occur in autoimmune disease states characterized by reduced thymic output or induction of lymphopenia. It has been clearly demonstrated that LIP of T cells occurs and plays a causative role in the development of autoimmune insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice [3]. Regulatory T cells (Tregs) are recognized as a major regulator of autoimmune diseases including IDDM in NOD mice [6,7,8], it has been suggested that both lymphopenia and Treg defects are precursors leading to autoimmune diseases [9,10]

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