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A Novel Role for CD4⁺ T Cells in the Control of Cachexia¹

Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

Cachexia is the dramatic weight loss and muscle atrophy seen in chronic disease states, including autoimmunity, cancer, and infection, and is often associated with lymphopenia. We have previously shown that CD4⁺ T cells that express the lowest density of CD44 (CD4⁺CD44^v.low) are significantly reduced in diabetic NOD mice that are cachexic compared with diabetic mice that are not cachexic. Using this model, and a model of cancer cachexia, we test the hypothesis that CD4⁺CD44^v.low cells play an active role in protecting the host from cachexia. CD4⁺CD44^v.low cells, but not CD4⁺ cells depleted of CD44^v.low cells, delay the onset of wasting when infused into either diabetic or prediabetic NOD recipients. However, no significant effect on the severity of diabetes was detected. In a model of cancer cachexia, they significantly reduce muscle atrophy, and inhibit muscle protein loss and DNA loss, even when given after the onset of cachexia. Protection from wasting and muscle atrophy by CD4⁺CD44^v.low cells is associated with protection from lymphopenia. These data suggest, for the first time, a role for an immune cell subset in protection from cachexia, and further suggest that the mechanism of protection is independent of protection from autoimmunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Diabetes National Research Group (DNRG0603), the Alzheimer’s and Ageing Research Center (AARC5104), and the National Institutes of Health (CA109729) to J.D.D.

² Current address: Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121.

³ Address correspondence and reprint requests to Dr. Joanna D. Davies, Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121. E-mail address: jdavies{at}tpims.org

⁴ Abbreviations used in this paper: TID, type 1 diabetes; BGL, blood glucose level; int, intermediate; LL2, Lewis lung carcinoma cell.