Reconstitution of double-negative T cells after cord blood transplantation and its predictive value for acute graft-versus-host disease

Background:With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation(UCBT),the correlation between immune reconstitution(IR)after UCBT and graft-versus-host disease(GVHD)has been reported successively,but reports on double-negative T(DNT)cell reconstitution and its association with acute GVHD(aGVHD)after UCBT are lacking.Methods:A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology,the First Affiliated Hospital of USTC,between August 2018 and June 2021.IR differences were compared between the patients with and without aGVHD.Results:The absolute number of DNT cells in the healthy Chinese population was 109(70-157)/μL,accounting for 5.82(3.98-8.19)%of lymphocytes.DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation.Importantly,the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year(F=4.684,P=0.039 and F=5.583,P=0.026,respectively).In addition,the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased,and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD(HR=0.46,95%confidence interval[CI]:0.23-0.93;P=0.031).Conclusions:Compared to the number of DNT cells in Chinese healthy people,the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow.In addition,the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.

Natural killer cells in tumor immunotherapy

Cancer is the second most common cause of death worldwide and remains one of the critical public health problems of our time1.Recently,immunotherapy has considerably improved the outcomes of patients with advanced cancers.Immune checkpoint blockade and chimeric antigen receptor(CAR)-T cell-based therapies have achieved remarkable success in recent decades,thus placing the host immune response in the spotlight as a potential new approach in antitumor therapy.

Activation of AMPKα1 is essential for regulatory T cell function and autoimmune liver disease prevention

Regulatory T cells(Treg cells)are crucial for maintaining immune tolerance.Compromising the regulatory function of Treg cells can lead to autoimmune liver disease.However,how Treg cell function is regulated has not been fully clarified.Here,we report that mice with AMP-activated protein kinase alpha 1(AMPKα1)globally knocked out spontaneously develop immune-mediated liver injury,with massive lymphocyte infiltration in the liver,elevated serum alanine aminotransferase levels,and greater production of autoantibodies.Both transplantation of wild-type bone marrow and adoptive transfer of wild-type Treg cells can prevent liver injury in AMPKα1-KO mice.In addition,Treg cell-specific AMPKα1-KO mice display histological features similar to those associated with autoimmune liver disease,greater production of autoantibodies,and hyperactivation of CD4^(+)T cells.AMPKα1 deficiency significantly impairs Treg cell suppressive function but does not affect Treg cell differentiation or proliferation.Furthermore,AMPK is activated upon T cell receptor(TCR)stimulation,which triggers Foxp3 phosphorylation,suppressing Foxp3 ubiquitination and proteasomal degradation.Importantly,the frequency of Treg cells and the phosphorylation levels of AMPK at T172 in circulating blood are significantly lower in patients with autoimmune liver diseases.Conclusion:Our data suggest that AMPK maintains the immunosuppressive function of Treg cells and confers protection against autoimmune liver disease.