CD4+ T cells regulate sickness-induced anorexia and fat wasting during a chronic parasitic infection

Catabolic responses of lean and fat energy stores are a component of the host response to infection. Cachexia is an extreme catabolic state characterized by unintentional weight loss and muscle loss, that can include fat loss. Whether cachexia plays any role in host defense or is a maladaptive consequence of host-pathogen interactions remains unknown. Traditionally studies have focused on understanding how inflammatory mediators and cells of the innate immune system contribute to the pathogenesis of cachexia and the depletion of energy stores. The cells of the adaptive immune system that regulate infection-induced cachexia remain elusive. In the present study, we examined the role of the adaptive immune response in cachexia pathogenesis using a murine model of the chronic parasitic infection Trypanosoma brucei, the causative agent of sleeping sickness. We found that the cachectic response occurs in two phases with the first stage occurring early in the infection and involved a loss of body fat mass associated with anorexia, and the second stage occurring later in the infection and involved a sustained loss of fat mass that was accompanied by lean mass wasting. CD4+ T cells were necessary for the development of the sickness-induced anorexic response during stage 1 of the infection, which led to adipose triglyceride lipase dependent lipolysis in adipocytes and the resulting fat wasting. Adipose tissue wasting had no impact on host resistance defenses or survival of infection, both of which were antibody-mediated and independent ofCD4+ T cell responses. Our work reveals a new mechanism for infection induced cachexia involving CD4+ T cell regulation of host feeding behavior and an unexpected decoupling of adaptive immune mediated resistance from the cachectic response during infection.