The Late Endosomal Transporter CD222 Directs the Spatial Distribution and Activity of Lck

Abstract

The spatial and temporal organization of T cell signaling molecules is increasingly accepted as a crucial step in controlling T cell activation. CD222, also known as the cation-independent mannose 6-phosphate/insulin-like growth factor 2 receptor, is the central component of endosomal transport pathways. In this study, we show that CD222 is a key regulator of the early T cell signaling cascade. Knockdown of CD222 hampers the effective progression of TCR-induced signaling and subsequent effector functions, which can be rescued via reconstitution of CD222 expression. We decipher that Lck is retained in the cytosol of CD222-deficient cells, which obstructs the recruitment of Lck to CD45 at the cell surface, resulting in an abundant inhibitory phosphorylation signature on Lck at the steady state. Hence, CD222 specifically controls the balance between active and inactive Lck in resting T cells, which guarantees operative T cell effector functions.

mTORC1 regulates mannose-6-phosphate receptor transport and T-cell vulnerability to regulatory T cells by controlling kinesin KIF13A

“…Despite great progress in T-cell biology, the function and regulation of M6PR in T cells remain poorly understood. Emerging evidence in the field associating M6PR to immune regulation [3, 22, 45] and also to immune dysregulation [24, 46] has led to renewed interests in exploring the role of M6PR in the immune system.…”

“…It also acts as a sink for insulin-like growth factor-II [18, 19] and promotes activation of the latent form of transforming growth factor-β [20]. M6PR is upregulated on activated T cells that possibly facilitates T-cell entry of inflammatory sites [21], and involved in T-cell activation through recruitment of lymphocyte-specific protein tyrosine kinase to the immunological synapse [22]. Moreover, we recently demonstrated a novel role for the M6PR in determining T-cell fate decisions during the contraction phase in Listeria monocytogenes -infected mice [3, 23].…”

“…A recent study reported that M6PR expression on T cells of untreated HIV-1-infected patients is significantly higher than healthy human controls, suggesting that perturbed T-cell memory compartment in HIV-1 patients may be associated with increased susceptibility of these T cells to Gzm-B-mediated cell apoptosis [24]. M6PR may thus represent a double-edged sword controlling both proliferation [22] and attrition [3, 23, 24] in T cells. Therefore, understanding the signals that regulate M6PR expression in T cells will have implication for modulating T-cell immunity in both infectious and autoimmune diseases [23, 24].…”

The mannose 6-phosphate/insulin-like growth factor 2 receptor mediates plasminogen-induced efferocytosis

“…Mouse M6P/IGF2R −/− fibroblasts were provided by Dr. E. Wagner (until 2008 ‐ IMP, Vienna, Austria; now CNIO, Madrid, Spain). M6P/IGF2R −/− fibroblasts stably expressing human M6P/IGF2R were prepared by retroviral infection . Mouse M6P/IGF2R‐negative mouse fibroblasts with or without expression of human M6P/IGF2R were used without any stimulation.…”

Editorial: Mannose-6-phosphate receptor delivers the death sentence

“…The receptor is largely distributed intracellularly, with only a fraction displayed at the cell surface, where it can act as a receptor for M6P-bearing proteins, including the serine protease GzmB [7]. M6PR is dramatically up-regulated on CD8 + T cells following activation [8], where this receptor has been shown to be involved in the recruitment of lymphocyte-specific protein tyrosine kinase to the immunologic synapse [9]. Ahmed et al [1] examined the expression of M6PR on transgenic CD8 + T cells (OT-I; specific for OVA-derived peptide) following LM-OVA infection.…”