The Goronzy Lab  

Current Research Projects

Mechanisms controlling T cell homeostasis

Adaptive immune responses depend on a T cell repertoire that is functionally balanced and has a diverse set of T cell receptors. T cell generation in the thymus peaks at puberty and then rapidly declines. T cell homeostasis is further threatened by T cell loss and antigen-driven oligoclonal T cell expansion. Of particular interest, latent infection with cytomegalovirus (CMV) causes hugely inflated T cell responses in some individuals. We are interested in examining mechanisms that maintain T cell homeostasis and prevent repertoire contraction with age, or that may fail as in the case of CMV infection.

T cell receptor calibration with age

T cell receptor activation thresholds are finely tuned, by positive and negative signaling loops, to allow the recognition of foreign antigens while maintaining tolerance to self. Receptor calibration is known to change during the life of a T cell: from thymocyte to na´ve T cell and effector and memory T cells. We are interested how age influences these signaling pathways and whether alterations in receptor calibration can be targeted to improve immune responses in the elderly.

T cell receptor calibration in autoimmunity

While signaling pathways can lose responsiveness with age and thus compromise immune competence, decreases in receptor threshold result in autoimmunity. We have evidence of altered receptor signaling pathways in T cells from patients with rheumatoid arthritis. Our current studies focus on how quantitative differences in signaling molecules influence signal processing and predispose for autoreactive immune responses.

Cellular metabolism and signal transduction in T cells

Metabolic pathways are closely interlinked with signaling pathways that control T cell activation, effector function and differentiation into functional T cell subsets and memory cells. We have described that declines in T helper cell function with age are in part caused by the dual specific phosphatase DUSP4 and the metabolic master regulator AMPK. We are interested how alterations in T cell metabolism with age influence T cell function.

Vaccine responses to varicella zoster vaccines

Reactivation of latent varicella zoster virus (VZV) infection is increasingly frequent after the age of 50 years, reflecting age-associated defects in T cell immunity. Vaccination with an attenuated virus is partly effective and we are using a systems biology approach to identify signatures that predict T and B cell responses in different age groups. The primary objective is to identify pathways that can be targeted to improve vaccine responses. As the vaccine contains live virus, these studies also provide a model system to understand immune responses to infections in the elderly.

Epigenetic regulation of T cell differentiation with age

We examine miRNA expression, DNA methylation and histone modification in different T cell populations to understand the influence of epigenetic mechanisms on altered T cell responses with age.

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