PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice

Valenzuela, Javier O.; Iclozan, Cristina; Hossain, M. Shahadat; Prlic, Martin; Hopewell, Emily L.; Bronk, Crystina C.; Wang, Junmei; Celis, Esteban; Engelman, Robert W.; Blazar, Bruce R.; Bevan, Michael J.; Waller, Edmund K.; Yu, Xue-Zhong; Beg, Amer A.

doi:10.1172/jci39692

Cited by 73 publications

(101 citation statements)

References 67 publications

(84 reference statements)

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“…Our findings are consistent with the fact that PKCu is a key molecule in modulating T cell activation versus anergy (48) and that PKCu effects are opposite to those of TGF-b. As PKCu relays a subset of CD28 signals during T cell activation, absence of PKCu raises the threshold for T cell activation and facilitates tolerance induction (48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

T Cell Activation Leads to Protein Kinase Cθ-Dependent Inhibition of TGF-β Signaling

Giroux

Delisle

O'Brien

et al. 2010

The Journal of Immunology

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TGF-β is an ubiquitous cytokine that plays a pivotal role in the maintenance of self-tolerance and prevention of immunopathologies. Under steady-state conditions, TGF-β keeps naive T cells in a resting state and inhibits Th1 and Th2 cell differentiation. Because rapid generation of Th1 and Th2 effector cells is needed in response to pathogen invasion, how do naive T cells escape from the quiescent state maintained by TGF-β? We hypothesized that stimulation by strong TCR agonists might interfere with TGF-β signaling. Using both primary mouse CD4+ T cells and human Jurkat cells, we observed that strong TCR agonists swiftly suppress TGF-β signaling. TCR engagement leads to a rapid increase in SMAD7 levels and decreased SMAD3 phosphorylation. We present evidence that TCR signaling hinders SMAD3 activation by inducing recruitment of TGF-βRs in lipid rafts together with inhibitory SMAD7. This effect is dependent on protein kinase Cθ, a downstream TCR signaling intermediary, as revealed by both pharmacological inhibition and expression of dominant-negative and constitutively active protein kinase Cθ mutants. This work broadens our understanding of the cross-talk occurring between the TCR and TGF-β signaling pathways and reveals that strong TCR agonists can release CD4 T cells from constitutive TGF-β signaling. We propose that this process may be of vital importance upon confrontation with microbial pathogens.

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Section: Discussionmentioning

confidence: 99%

T Cell Activation Leads to Protein Kinase Cθ-Dependent Inhibition of TGF-β Signaling

Giroux

Delisle

O'Brien

et al. 2010

The Journal of Immunology

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“…Mice lacking CD18 or CCR7 also exhibit effective GVL activity associated with absent or attenuated GVHD responses (50,51), as do mice lacking PKCθ (52). While these models are superficially similar, closer examination reveals important differences.…”

Section: Methodsmentioning

confidence: 99%

“…For example, Ccr7 -/-T cells show defects in trafficking to recipient lymph nodes, while Cd18 -/-T cells migrate efficiently to lymph nodes but are defective in their ability to enter inflamed skin and GVHD target tissues such as intestine (50,53). PKCθ deficiency was shown to affect GVHD via altered T cell effector function (52), but trafficking may also be affected, since PKCθ is known to regulate RAP1 activation and T cell trafficking in other settings (16,54). CRK-deficient T cells, which migrate efficiently to lymphoid organs but inefficiently to liver in a GVHD model, most closely resemble the Cd18 -/-T cells.…”

Section: Methodsmentioning

confidence: 99%

CRK proteins selectively regulate T cell migration into inflamed tissues

Huang¹,

Clarke²,

Karimi³

et al. 2015

J. Clin. Invest.

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R e s e a R c h a R t i c l e1 0 2 0 jci.org Volume 125 Number 3 March 2015 therapeutic implications, since they can carry out graftversus-leukemia (GVL) responses with minimal GVHD. Results Generation and characterization of T cell-specific CRK T cells (data not shown).Western blotting of purified CD4 + T cells from Dko and WT mice revealed that levels of CRKI, CRKII, and CRKL in the mutant T cells were reduced by at least 95% ( Figure 1A and data not shown), and flow cytometric analysis confirmed loss of CRK protein expression (Figure 1, B and C).CRK/CRKL Dko mice were born at Mendelian ratios, and spleen, thymus, and lymph nodes exhibited normal cellularity (data not shown). Thymocyte populations were similar in WT and Dko mice, indicating that T cell development proceeded normally ( Figure 1D). Peripheral lymphoid organs showed no differences in proportions of CD4 + and CD8 + T cells, naive (CD62L hi CD44 lo ), memory (CD62L lo CD44 hi ), or activated (CD69 hi ) T cell subsets (Figure 1, D and E, and data not shown). Thus, these mice represented a suitable source of mature CRK/CRKL Dko T cells for functional studies. CRK/CRKL-deficient T cells show defects in adhesion and polarization.Since CRK proteins control adhesion in non-hematopoietic cells (4), we first asked whether integrin-dependent adhesion is defective in CRK/CRKL Dko T cells. On plates coated with ICAM-1, the ligand for the β 2 integrin LFA-1, WT preactivated CD4 + T cells showed about 10% basal binding, which was increased 2-to 5-fold after stimulation with the chemokines CXCL12 or CCL21, or anti-CD3 (Figure 2A). CRK/CRKL Dko T cells showed a significant reduction in adhesion to ICAM-1 under both basal and stimulated conditions. Indeed, chemokine stimulation induced almost no increased adhesion in these cells. Treatment with PMA bypassed the defect. This is most likely because the defect in CRK/CRKL Dko cells lies upstream of PKC signaling in the pathway leading to integrin activation, though PKC activation could also drive a parallel

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“…However, recent studies suggest that the threshold of T cell responses needed to eradicate leukemia cells is different from the responses threshold required for mediating GVHD. For example, a recent study showed that PKCu was crucial for the expansion of alloreactive T cells, and inhibition of PKCu could reduce GVHD while preserving the GVL effect (54). In addition, studies showed that the elimination of residual leukemia was primarily mediated by donor CD8 + cytotoxic T lymphocytes and NK cells, whereas the inflammatory cytokines that are secreted mainly by CD4 + Th cells have a very limited role in leukemia eradication but contribute significantly to the toxicity of GVHD (55).…”

Section: Discussionmentioning

confidence: 99%

Valproic Acid Ameliorates Graft-versus-Host Disease by Downregulating Th1 and Th17 Cells

Long

Chang

Shen

et al. 2015

The Journal of Immunology

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Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation. Valproic acid (VPA) was described as a histone deacetylase inhibitor that had anti-inflammatory effects and reduced the production of proinflammatory cytokines in experimental autoimmune disease models. Using well-characterized mouse models of MHC-mismatched transplantation, we studied the effects of VPA on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of VPA significantly attenuated the clinical severity of GVHD, the histopathology of GVHD-involved organs, and the overall mortality from GVHD. VPA downregulated Th1 and Th17 cell responses and cytokine production in vitro and in vivo, whereas its effect on GVHD was regulatory T cell independent. The effect of VPA was related to its ability to directly reduce the activity of Akt, an important regulator of T cell immune responses. Importantly, when mice received lethal doses of host-type acute leukemia cells, administration of VPA did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a unique role for VPA as a histone deacetylase inhibitor in reducing the donor CD4+ T cells that contribute to GVHD, which may provide a strategy to reduce GVHD while preserving the GVL effect.

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PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice

Cited by 73 publications

References 67 publications

T Cell Activation Leads to Protein Kinase Cθ-Dependent Inhibition of TGF-β Signaling

T Cell Activation Leads to Protein Kinase Cθ-Dependent Inhibition of TGF-β Signaling

CRK proteins selectively regulate T cell migration into inflamed tissues

Valproic Acid Ameliorates Graft-versus-Host Disease by Downregulating Th1 and Th17 Cells

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