CD5-Dependent CK2 Activation Pathway Regulates Threshold for T Cell Anergy

Abstract

CD5 activates CK2, a serine/threonine kinase that constitutively associates with the CK2-binding domain at the end of its cytoplasmic tail. To determine the physiological significance of CD5-dependent CK2 activation in T-cells we generated a knock-in mouse that expresses a CD5 protein containing a microdeletion with selective inability to interact with CK2 (CD5ΔCK2BD). The levels of CD5 on developing and mature T-cell populations from CD5ΔCK2BD mice and CD5WT mice were similar. The thymus of CD5ΔCK2BD mice contained fewer double positive (DP) thymocytes than that of both CD5WT and CD5KO mice, though the numbers of all other immature and mature T-cell populations were unaltered. CD5ΔCK2BD T-cells hypoproliferated and exhibited enhanced AICD when stimulated with anti-CD3 or cognate peptide in comparison to CD5WT T-cells. We also found that functional CD5-dependent CK2 signaling was necessary for efficient differentiation of naïve CD4+ T-cells into Th2 and Th17 cells, but not Th1 cells. We previously showed that experimental autoimmune encephalomyelitis (EAE) in CD5KO mice was less severe and delayed in onset than in CD5WT mice. Remarkably, CD5ΔCK2BD mice recapitulated both EAE severity and disease onset of CD5KO mice. Increasing the immunization dose of myelin oligodendrocyte (MOG35-55) peptide, a model that mimics high dose tolerance, led to decreased severity of EAE in CD5 WT mice but not in CD5KO or CD5ΔCK2BD mice. This property was recapitulated in in vitro re-stimulation assays. These results demonstrate that CD5-CK2 signaling sets the threshold for T-cell responsiveness and it is necessary for efficient generation of Th2 and Th17 cells.

Phenotypic Variation in Aicardi–Goutières Syndrome Explained by Cell-Specific IFN-Stimulated Gene Response and Cytokine Release

“…2C). This method enumerates the proportion of cells progressing through the cell cycle during the short pulse labeling and therefore overcomes confounders such as cell death (37). We found that the proportion of EdU + cells was significantly reduced in TREX1 shRNA-transduced cells (p , 0.05, Fig.…”

Inhibition of System Xc− Transporter Attenuates Autoimmune Inflammatory Demyelination

“…MOG 35-55 -specific (MOGp) Th1 and Th17 cells were generated as described previously (23, 24). Briefly, splenocytes and draining lymph node cells were obtained from male C57Bl/6 mice 12 d post-immunization with 150 μg MOGp (CPC Scientific, San Jose, CA) in complete Freund's adjuvant.…”

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

“…Furthermore, the CD5 receptor has also been described to contribute to cell survival through association of its C-terminal cytoplasmic region with the serine/threonine kinase CK2 [47,48]. Thus, the CD5-dependent CK2 activation would deliver anti-apoptotic signals likely involved in homeostatic T-and B1a-cell survival and eventually resistance to activation-induced cell death (AICD) [49].…”

“…Furthermore, the CD5 receptor has also been described to contribute to cell survival through association of its C-terminal cytoplasmic region with the serine/threonine kinase CK2 [47,48]. Thus, the CD5-dependent CK2 activation would deliver anti-apoptotic signals likely involved in homeostatic T-and B1a-cell survival and eventually resistance to activation-induced cell death (AICD) [49].The inhibitory signaling ability of CD5 has been linked to its cytoplasmic tail and more specifically to tyrosines embedded in the proximal region of the membrane [50] or the pseudoimmunoreceptor tyrosine-based motif [51,52]. Such a negative immunomodulatory ability positions CD5 as a putative "immune checkpoint regulator" in a similar way to that reported for cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1), among others, whose blockade has open up new pathways for cancer immunotherapy [53].…”

“…1A, [61]). This was attributed to differential FasL expression regulation by CD5, since CD5 low cells expressed higher levels of FasL and consequently presented higher caspase-8 activity, though the contribution of CD5-dependent CK2 pro-survival activity [49,52] should also be taken into consideration [62]. Indeed, CD5 knock-out mice exhibited slow tumor growth coupled to increased T-cell activation marker expression (e.g., CD25 and CD69) by TILs (Fig.…”