Mannose-6-Phosphate Receptor, a Novel Checkpoint for T cell Expansion, is expressed at High Levels on T cells from Untreated HIV+ Patients

Recently, we showed that untreated patients with HIV infection display high peripheral blood counts of regulatory B cells expressing the serine protease granzyme B (GrB) in the absence of perforin (GraB cells) [1]. Importantly, these GraB cells are able to directly regulate proliferation and survival of T cells both in-vitro and in- vivo. The mechanism of action involves a perforin-independent transfer of GrBto T cells and GrB-dependent degradation of the T cell receptor ζ-chain in T cells [1,2]. A known receptor for GrB, which acts in a perforin-independent manner, is the mannose-6-phosphate receptor (M6PR, CD222), which has been shown to mediate GrB uptake and regulation of M6PR-expressing target cells [3,4]. A recent study in Listeria-infected mice demonstrated that the differential expression of M6PR on cytotoxic T cells is directly linked to their survival and proliferative capacity [5]. M6PR therefore appears to represent an important check point for T cell expansion and memory T cell formation after systemic infections.