Polarity gene discs large homolog 1 regulates the generation of memory T cells

Abstract

SUMMARY Mammalian ortholog of Drosophila cell polarity protein, Dlg1, plays a critical role in neural synapse formation, epithelial cell homeostasis, and urogenital development. More recently, it has been proposed that Dlg1 may also be involved in the regulation of T-cell proliferation, migration, and antigen receptor signaling. However, a requirement for Dlg1 in development and function of T lineage cells remains to be established. In this study, we investigated a role for Dlg1 during T-cell development and function using a combination of conditional Dlg1 knockout and two different Cre expression systems where Dlg1 deficiency is restricted to the T-cell lineage only, or all hematopoietic cells. Here, using three different TCR models, we show that Dlg1 is not required during development and selection of thymocytes bearing functionally rearranged TCR transgenes. Moreover, Dlg1 is dispensable in the activation and proliferative expansion of antigen specific TCR transgenic CD4+ and CD8+ T cells in vitro and in vivo. Surprisingly, however, we show that Dlg1 is required for normal generation of memory T cells during endogenous response to cognate antigen. Thus, Dlg1 is not required for the thymocyte selection or the activation of primary T cells, however it is involved in the generation of memory T cells.

The Scribble–Dlg–Lgl Module in Cell Polarity Regulation

“…These studies indicate a novel role for Dlg1 in PCP signaling. Dlg1 loss in the mouse also impacts on non-epithelial tissues such as T lymphocytes (Stephenson et al 2007;Humphries et al 2012;Gmyrek et al 2013). Interestingly, closer scrutiny of Dlg3 mice showed low penetrance embryonic lethality, associated with open brain phenotype and cochlear inner ear cell defects, also suggesting a role in PCP signaling (Van Campenhout et al 2011).…”

Selective Phosphorylation of the Dlg1AB Variant Is Critical for TCR-Induced p38 Activation and Induction of Proinflammatory Cytokines in CD8+ T Cells

“…Despite growing evidence for Dlg1 in specifying signal transduction downstream of the TCR, recent attempts by numerous groups to extend these studies to knockout models have been inconsistent and largely unavailing (36,43,44). The mild phenotype seen in these models is attributed to compensation of other Dlg1 family members; such as PSD-95, which is known to have functional redundancy with Dlg1 in neurons (37).…”

“…In CD4 + effector cells, Dlg1 is thought to play a role in skewing toward expression of Th1 cytokines (36). In addition, Dlg1 also has been shown to influence the development of CD4 + T cell memory (44). Although both Dlg1AB and Dlg1B are expressed in CD4 + T cell subsets, the relative abundance of each isoform and the role of phosphorylation have yet to be explored (O. Silva et al, submitted for publication).…”

Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs

“…Mice footpad immunizations have been previously described [8], [14]. Briefly, SIINFEKL diluted in PBS and CFA was emulsified with the interchangeable syringes connected with micro-emulsified (18G) needle (Popper & Sons).…”

“…For evaluation of IL-12p40 expression ex vivo , pre-sorted (to exclude CD3ε, panNK, CD19 and Ter119) CD11c + DCs from draining lymph nodes of immunized mice were stimulated with CpG1826 (1 µM) for 6 hrs in the presence of brefeldin A and fixed and permeabilized cells were stained for IL-12p40 within Mo-DCs (CD11c + CD11b + Ly6C + MHCII + ) and CD8α DCs (CD11c + CD8α + ). To evaluate IFNγ production by re-stimulated cells isolated from draining lymph nodes, an ELISPOT was employed as described previously [8], [14]. Briefly, 96-plates with immobilon-P membrane were coated overnight with primary IFNγ Ab.…”