Investigation of the Effects of IL-2 on the Frequency of FcRL3+ Tregs and T cell Activation in HIV-infected Patients
Basic Science Award
Regulatory T cells (Tregs), defined by expression of FoxP3 and the IL-2 receptor CD25, play a critical role in self-tolerance and suppressing immune responses elicited against infectious agents such as HIV. As it is now recognized that some of the immunopathology wrought by HIV infection may be due to aberrant immune activation, much focus is centered on the role of Tregs and how they may decrease immune activation and slow disease progression. Treatment of HIV-infected patients with IL-2 has shown promise in boosting polyclonal T cell numbers, and some of these effects may be due to Treg expansion, thus dampening immune activation to allow T cell reconstitution. We have identified a subset of Tregs that expresses a newly identified protein, Fc receptor-like protein 3 (FcRL3). FcRL3 is an autoimmune susceptibility gene; patients with a T/C polymorphism at position -169 (conferring higher expression of the protein) are at increased risk of several autoimmune conditions. We find that FcRL3+ Tregs exhibit a senescent phenotype, are functionally defective, and have reduced responses to TCR+IL-2 induced proliferation in vitro compared to FcRL3- Tregs. The aim of our study is to examine the effects of IL-2 on the dynamics of FcRL3+ Tregs and T cell activation levels in HIV-infected patients. Pre-and post- IL-2 treatment and matched untreated control samples from archived specimens of HIV-infected patients will be analyzed by flow cytometry for T cell/ Treg subsets, FcRL3 expression, and markers of immune activation, and then screened by PCR for their FcRL3 -169C/T genotype. Data will be analyzed statistically by cross sectional and longitudinal comparisons to determine whether IL-2 exerts a significant effect on the frequency of FcRL3+ Tregs, and whether the frequency of FcRL3+ Tregs is correlated to levels of T cell activation. This work will permit greater understanding of Treg dynamics in HIV disease.