CD5-CK2 Signaling Modulates Erk Activation and Thymocyte Survival

Abstract

CD5 is well recognized for its importance in thymic selection. Although this property of CD5 has been attributed to its ITIM-domain dependent regulation of TCR-signal strength, the mechanism has not been established. A second major signaling domain within the cytoplasmic tail of CD5 is a CK2 binding/activation domain (CD5-CK2BD). Using a gene-targeted mouse in which the CD5-CK2BD is selectively ablated (CD5-ΔCK2BD), we determined that loss of function of CD5-CK2 signaling in a MHC-II selecting TCR transgenic (OT-II) mouse resulted in decrease in double positive (DP) thymocytes, which correlated with enhanced apoptosis. Remarkably, DP cells expressing high levels of CD5 and CD69 and single positive (CD4+SP) thymocytes were increased in CD5-ΔCK2BD mice indicating that CD5-CK2 signaling regulates positive selection and promotes survival. Consistent with this possibility, we determined that the activation and nuclear localization of ERK as well as apoptosis was greater in thymic populations from OTII CD5-ΔCK2BD mice than OTII CD5-WT mice following injection of OVA323-339-peptide. The mobilization of Ca2+, an early event of TCR activation, was not altered by the loss of CD5-CK2 signaling. Collectively, these data demonstrate that the CD5-CK2 signaling axis regulates positive selection by modulating activation of ERK and promoting survival independent of proximal TCR signals.

The multiple faces of CD5

“…Interestingly, these IL‐23R induction does not seem to be dependent of the CD5‐CK2 mediated signaling suggesting alternative pathways through which CD5 can regulate IL‐17/Th17 generation. Regarding the role of the CK2‐binding domain of CD5 in Treg generation, it was reported that the absence of this domain did not affect tTreg generation; however, unpublished data from our group (Burgueño‐Bucio et al., in preparation) suggest that this domain does have an impact in iTreg generation.…”

“…61 By using CD5-deficient mice, it was demonstrated that thymi development. 63 This experiment showed that the inability of CD5 to bind CK2 during thymic development results in an increased generation of CD4+ T cells at the expense of a reduced number of DP cells. This shift in the thymic subpopulations is the result of at least two combined effects: First, the absence of the CD5-CK2 binding region results in an increased apoptosis of DP cells, although it also affects CD4+ T cells and CD8+ T cells; and second, the absence of this domain increased pERK levels which results in altered negative and positive selection processes.…”

“…Using a gene‐targeted mouse in which the CD5‐CK2 binding domain was selectively ablated, Mier et al. determined the functional role of this domain in T cell survival during thymic development . This experiment showed that the inability of CD5 to bind CK2 during thymic development results in an increased generation of CD4+ T cells at the expense of a reduced number of DP cells.…”

“…This experiment showed that the inability of CD5 to bind CK2 during thymic development results in an increased generation of CD4+ T cells at the expense of a reduced number of DP cells. This shift in the thymic subpopulations is the result of at least two combined effects: First, the absence of the CD5‐CK2 binding region results in an increased apoptosis of DP cells, although it also affects CD4+ T cells and CD8+ T cells; and second, the absence of this domain increased pERK levels which results in altered negative and positive selection processes . Interestingly, increased pERK levels did not correlate with increased TCR proximal signaling, thus suggesting that the CD5‐CK2 binding domain, in addition to regulating thymocyte survival, modulates TCR signaling by an alternative noncanonical pathway (Fig.…”

CD5 blockade enhances ex vivo CD8+ T cell activation and tumour cell cytotoxicity

“…ERK2 regulates CD8 + T cell proliferation and survival . ERK phosphorylation can be elevated in the absence of CD5‐CK2 signalling . To determine if administration of anti‐CD5 MAb could lead to impaired CD5 signalling and increased ERK activation, splenocytes isolated from tumour‐naïve mice and treated with anti‐CD3 plus anti‐CD5 MAbs showed increased phosphorylation of ERK1/2, but not cells receiving anti‐CD3 MAb alone (Fig.…”