Tu109 - CD2-high Auto-reactive, but Not Viral-reactive, Memory CD8 T Cell Repopulation Is Hampered Following LFA3-Ig Depletion

Alice Wiedeman – Benaroya Research Institute; Carolina Acosta-Vega – Benaroya Research Institute; Lauren Higdon – Immune Tolerance Network; Srinath Sanda – Immune Tolerance Network

Abstract Text: Alefacept is an LFA3-Ig drug that slowed loss of beta cell function in recent onset type 1 diabetic (T1D) individuals in the T1DAL trial. Alefacept depletes CD2-high cells, but its effect on autoreactive CD8 T cells has not been described. We used mass and flow cytometry with Class I peptide-MHC tetramers on clinical and in in vitro depletion assays to count and characterize the CD8 population during alefacept therapy. We found that memory CD8 T cells (Tmem) in healthy and T1D individuals include both CD2-high and CD2-low subsets, all of which express higher levels than naïve CD8 T cells. CD2-high Tmem included central and effector memory, CD57+, and exhausted subsets while CD2-low memory and CD57 populations express Helios. Islet-specific cells were enriched in this Helios+ CD2-low Tmem population. CD2-high viral and islet specific CD8 Tmem were depleted with alefacept therapy both in vivo and in vitro. However, overall depletion of islet-specific Tmem was not significant due to their prevalence in the CD2-low population that was not depleted. Two years following treatment, CD2-high total and viral specific CD8 Tmem rebounded but islet specific cells did not. This lack of rebound among CD2-high islet-specific Tmem did not associate with clinical response, nor did it appear to be due to a natural decline over time as determined by comparison to placebo data. Together, these data suggest that islet-specific CD8 T cells are enriched for a Helios+ CD2-low Tmem subset that is not depleted by alefacept but also does not preferentially expand following treatment.