Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosal sites. Here we found that CD4+ T cells are important for the formation of functional lung-resident CD8+ ...T cells after influenza virus infection. In the absence of CD4+ T cells, CD8+ T cells displayed reduced expression of CD103 (Itgae), were mislocalized away from airway epithelia, and demonstrated an impaired ability to recruit CD8+ T cells to the lung airways upon heterosubtypic challenge. CD4+ T cell-derived interferon-γ was necessary for generating lung-resident CD103+ CD8+ Trm cells. Furthermore, expression of the transcription factor T-bet was increased in “unhelped” lung Trm cells, and a reduction in T-bet rescued CD103 expression in the absence of CD4+ T cell help. Thus, CD4+ T cell-dependent signals are important to limit expression of T-bet and allow for the development of CD103+ CD8+ Trm cells in the lung airways following respiratory infection.
Display omitted
•CD4+ T cells help the development of flu-specific CD103+ CD8+ Trm cells•CD4+ T cell-derived IFN-γ is necessary for generating lung CD8+ Trm cells•T-bet represses lung CD8+ Trm cell formation and induction of CD103 by TGF-β•Reduction of T-bet restores CD103 expression on “unhelped” CD8+ T cells
Tissue-resident memory T (Trm) cells protect against infection at mucosal sites. Craft and colleagues show that during viral infection, CD4+ T cell-dependent signals limit T-bet expression and allow CD103 upregulation necessary for Trm cell formation in the lung.
Protein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of T cell differentiation, proliferation, metabolism, and survival. Here, we show that ...during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) in vivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhibitor rapamycin. FoxO1 functioned as a transcriptional activator of PD-1 that promoted the differentiation of terminally exhausted CTLs. Importantly, FoxO1-null CTLs failed to persist and control chronic viral infection. Collectively, this study shows that CTLs adapt to persistent infection through a positive feedback pathway (PD-1→FoxO1→PD-1) that functions to both desensitize virus-specific CTLs to antigen and support their survival during chronic viral infection.
Display omitted
•TCR activation of AKT and mTOR is impaired in exhausted CTLs•Therapeutic blockade of PD-1 signaling is mTOR dependent•FoxO1 is necessary to sustain CTL responses and control chronic viral infection•FoxO1 regulates the expression and differentiation of PD-1hi exhausted CTLs
Chronic infection can lead to a state of CD8+ T cell dysfunction referred to as exhaustion. Kaech and colleagues show that the transcription factor FoxO1 promotes the differentiation and maintenance of exhausted CD8+ T cells to control chronic viral infection.
Follicular helper T (Tfh) cells are required for the establishment of T-dependent B cell memory and high affinity antibody-secreting cells. We have revealed herein opposing roles for signal ...transducer and activator of transcription 3 (STAT3) and type I interferon (IFN) signaling in the differentiation of Tfh cells following viral infection. STAT3-deficient CD4+ T cells had a profound defect in Tfh cell differentiation, accompanied by decreased germinal center (GC) B cells and antigen-specific antibody production during acute infection with lymphocytic choriomeningitis virus. STAT3-deficient Tfh cells had strikingly increased expression of a number of IFN-inducible genes, in addition to enhanced T-bet synthesis, thus adopting a T helper 1 (Th1) cell-like effector phenotype. Conversely, IFN-αβ receptor blockade restored Tfh and GC B cell phenotypes in mice containing STAT3-deficient CD4+ T cells. These data suggest mutually repressive roles for STAT3 and type I IFN signaling pathways in the differentiation of Tfh cells following viral infection.
Display omitted
•STAT3 is required for Tfh and GC B cell differentiation•STAT3-deficient Tfh cells have a transcriptome similar to Th1 cells•Blockade of type I IFNs rescues STAT3-deficient Tfh cell development and function•Type I IFNs promote STAT5 binding over that of STAT3 at the Bcl6 locus
CD4
+ T cells differentiate into multiple effector types, but it is unclear how they form memory T cells during infection in vivo. Profiling virus-specific CD4
+ T cells revealed that effector cells ...with T helper 1 (Th1) or T follicular helper (Tfh) cell characteristics differentiated into memory cells, although expression of Tfh cell markers declined over time. In contrast to virus-specific effector CD8
+ T cells, increased IL-7R expression was not a reliable marker of CD4
+ memory precursor cells. However, decreased Ly6C and T-bet (
Tbx21) expression distinguished a subset of Th1 cells that displayed greater longevity and proliferative responses to secondary infection. Moreover, the gene expression profile of Ly6C
loT-bet
int Th1 effector cells was virtually identical to mature memory CD4
+ T cells, indicating early maturation of memory CD4
+ T cell features in this subset during acute viral infection. This study provides a framework for memory CD4
+ T cell development after acute viral infection.
Display omitted
► Increased IL-7R expression does not mark CD4
+ memory precursor cells ► T-bet acts in a graded manner to regulate formation of Th1 and Tfh cell subsets ► Ly6C
loT-bet
int Th1 effector CD4
+ cells have enhanced longevity and recall responses ► Ly6C
loT-bet
int Th1 effector and memory CD4
+ cells share similar gene expression
The differentiation of CD4+ helper T cell subsets with diverse effector functions is accompanied by changes in metabolism required to meet their bioenergetic demands. We find that follicular B helper ...T (Tfh) cells exhibited less proliferation, glycolysis, and mitochondrial respiration, accompanied by reduced mTOR kinase activity compared to T helper 1 (Th1) cells in response to acute viral infection. IL-2-mediated activation of the Akt kinase and mTORc1 signaling was both necessary and sufficient to shift differentiation away from Tfh cells, instead promoting that of Th1 cells. These findings were not the result of generalized signaling attenuation in Tfh cells, because they retained the ability to flux calcium and activate NFAT-transcription-factor-dependent cytokine production. These data identify the interleukin-2 (IL-2)-mTORc1 axis as a critical orchestrator of the reciprocal balance between Tfh and Th1 cell fates and their respective metabolic activities after acute viral infection.
Display omitted
•Tfh cells are less proliferative and metabolically active than Th1 cells•NFAT signaling is conserved in Tfh cells•Tfh cells have minimal mTOR activity and are intact in the absence of mTORc1•IL-2 suppresses Tfh cell differentiation through Akt activation
Differentiation of CD4+ helper T cells is accompanied by changes in metabolism required to meet their bioenergetic demands. Craft and colleagues demonstrate that the interleukin-2 (IL-2)-mTOR axis is a critical orchestrator of the reciprocal balance between follicular B helper T cell and T helper 1 cell fates.
The transcription factor T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory ...precursor cells during viral infection. We find that, at high concentrations, T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential.
Type 1 IFNs get induced by viral nucleic acids and proteins acting on cellular signaling molecules such as Toll-like receptors and RNA helicases, which, in turn, release transcription factors into ...the nucleus. T cells that are exposed to their cognate peptide antigen presented in the context of MHC (pMHC) on APC-like dendritic cells (DCs) get costimulated through receptors such as CD28 and CD40 ligand and undergo a differentiation program associated with several cycles of division, the expression of the transcription factors t-bet and eomesodermin, followed by the acquisition of effector functions (Figure 1D).
Summary
Ibrutinib is effective in patients with chronic lymphocytic leukaemia (CLL); however, treatment resistance remains a problem. Ublituximab is a novel, glycoengineered anti‐CD20 monoclonal ...antibody with single‐agent activity in relapsed CLL. We report the results of a phase 2 study evaluating combination therapy with ibrutinib and ublituximab in patients with relapsed or refractory CLL. Patients received ibrutinib 420 mg once daily. Ublituximab was administered on days 1, 8 and 15 of cycle 1 followed by day 1 of cycles 2–6. Response assessments were completed at cycles 3 and 6; patients then continued on ibrutinib monotherapy per standard of care. Forty‐one of 45 enrolled patients were evaluable for efficacy. Safety was consistent with prior experience for each drug, with infusion reactions the most prevalent adverse event. Combination therapy resulted in an overall response rate (ORR) of 88% at 6 months. In the 20 patients with high‐risk features (17p or 11q deletions or TP53 mutation) and evaluable for efficacy, the ORR was 95%, with three patients (15%) achieving negative minimal residual disease. Median time to response was 8 weeks. Ublituximab in combination with ibrutinib resulted in rapid and high response rates. The long‐term clinical benefit of ublituximab will be defined by an ongoing phase 3 trial (NCT 02301156).
T follicular helper cells (Tfh) are crucial for the initiation and maintenance of germinal center (GC) reactions and high affinity, isotype-switched antibody responses. In this study, we demonstrate ...that direct TGF-β signaling to CD4 T cells is important for the formation of influenza-specific Tfh cells, GC reactions, and development of isotype-switched, flu-specific antibody responses. Early during infection, TGF-β signaling suppressed the expression of the high affinity IL-2 receptor α chain (CD25) on virus-specific CD4 T cells, which tempered IL-2 signaling and STAT5 and mammalian target of rapamycin (mTOR) activation in Tfh precursor CD4 T cells. Inhibition of mTOR allowed for the differentiation of Tfh cells in the absence of TGF-βR signaling, suggesting that TGF-β insulates Tfh progenitor cells from IL-2-delivered mTOR signals, thereby promoting Tfh differentiation during acute viral infection. These findings identify a new pathway critical for the generation of Tfh cells and humoral responses during respiratory viral infections.
PDF
