Abstract:While inhibition of T cell co-inhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. Type 1 interferon (IFN-I) modulates T cell immunity in viral infection, autoimmunity, and cancer, and may facilitate induction of T cell exhaustion in chronic viral infection1,2. Here we show that IFN-I regulates co-inhibitory receptors expression on human T cells, inducing PD-1/TIM-3/LAG-3 while surprisingly inhibiting TIGIT expression. High… Show more
“…For instance, TCF7 sustained to play roles in W1 and W2, consistent with its critical role in transition from naive to pre-dysfunction state. 31 SP140 , which was related to T cell dysfunction by regulating co-inhibitory receptors LAG3 and TIGIT in viral infection, 32 played a regulatory role continuously from W1 to W3. Figure 5 Dynamic regulatory pattern of transcription factors (A) Median Spearman correlation of TF-target pairs within each window calculated in the four windows respectively.…”
T cells exhibit heterogeneous functional states, which correlate with responsiveness to immune checkpoint blockade and prognosis of tumor patients. However, the molecular regulatory mechanisms underlying the dynamic process of T cell state transition remain largely unknown. Based on single-cell transcriptome data of T cells in non-small cell lung cancer, we combined cell states and pseudo-times to propose a pipeline to construct dynamic regulatory networks for dissecting the process of T cell dysfunction. Candidate regulators at different stages were revealed in the process of tumor-infiltrating T cell dysfunction. Through comparing dynamic networks across the T cell state transition, we revealed frequent regulatory interaction rewiring and further refined critical regulators mediating each state transition. Several known regulators were identified, including
TCF7
,
EOMES
,
ID2
, and
TOX
. Notably, one of the critical regulators,
TSC22D3
, was frequently identified in the state transitions from the intermediate state to the pre-dysfunction and dysfunction state, exerting diverse roles in each state transition by regulatory interaction rewiring. Moreover, higher expression of
TSC22D3
was associated with the clinical outcome of tumor patients. Our study embedded transcription factors (TFs) within the temporal dynamic networks, providing a comprehensive view of dynamic regulatory mechanisms controlling the process of T cell state transition.
“…For instance, TCF7 sustained to play roles in W1 and W2, consistent with its critical role in transition from naive to pre-dysfunction state. 31 SP140 , which was related to T cell dysfunction by regulating co-inhibitory receptors LAG3 and TIGIT in viral infection, 32 played a regulatory role continuously from W1 to W3. Figure 5 Dynamic regulatory pattern of transcription factors (A) Median Spearman correlation of TF-target pairs within each window calculated in the four windows respectively.…”
T cells exhibit heterogeneous functional states, which correlate with responsiveness to immune checkpoint blockade and prognosis of tumor patients. However, the molecular regulatory mechanisms underlying the dynamic process of T cell state transition remain largely unknown. Based on single-cell transcriptome data of T cells in non-small cell lung cancer, we combined cell states and pseudo-times to propose a pipeline to construct dynamic regulatory networks for dissecting the process of T cell dysfunction. Candidate regulators at different stages were revealed in the process of tumor-infiltrating T cell dysfunction. Through comparing dynamic networks across the T cell state transition, we revealed frequent regulatory interaction rewiring and further refined critical regulators mediating each state transition. Several known regulators were identified, including
TCF7
,
EOMES
,
ID2
, and
TOX
. Notably, one of the critical regulators,
TSC22D3
, was frequently identified in the state transitions from the intermediate state to the pre-dysfunction and dysfunction state, exerting diverse roles in each state transition by regulatory interaction rewiring. Moreover, higher expression of
TSC22D3
was associated with the clinical outcome of tumor patients. Our study embedded transcription factors (TFs) within the temporal dynamic networks, providing a comprehensive view of dynamic regulatory mechanisms controlling the process of T cell state transition.
“…One of the common signals between the acute phase of COVID-19 and chronic autoimmune conditions such as SLE are type-1 interferon (IFN) signatures 5,35,36 . Type-1 IFN (IFN-I) is reported to downregulate CXCR5 expression on human T cells 37 and our recent data showed that IFN-I upregulates PD-1 expression and downregulates CXCR5 expression in an in vitro assay 38 . Intriguingly, most of the genes unique to PD-1 high CXCR5 − Tph cells such as CXCR6, LAG3, ZBTB20 , and CHD7 had the same directions for their expression levels after type-1 IFN stimulation 38 .…”
Section: Discussionmentioning
confidence: 99%
“…Type-1 IFN (IFN-I) is reported to downregulate CXCR5 expression on human T cells 37 and our recent data showed that IFN-I upregulates PD-1 expression and downregulates CXCR5 expression in an in vitro assay 38 . Intriguingly, most of the genes unique to PD-1 high CXCR5 − Tph cells such as CXCR6, LAG3, ZBTB20 , and CHD7 had the same directions for their expression levels after type-1 IFN stimulation 38 . These data indicate that type-1 IFN might be one of the key signals to induce these Tph cells.…”
SummaryA dysregulated immune response against coronavirus-2 (SARS-CoV-2) plays a critical role in the outcome of patients with coronavirus disease 2019 (COVID-19). A significant increase in circulating plasmablasts is characteristic of COVID-19 though the underlying mechanisms and its prognostic implications are not known. Here, we demonstrate that in the acute phase of COVID-19, activated PD-1highCXCR5−CD4+ T cells, peripheral helper T cells, (Tph) are significantly increased and promote inflammatory tissue-homing plasmablasts in patients with stable but not severe COVID-19. Analysis of scRNA-seq data revealed that plasmablasts in stable patients express higher levels of tissue-homing receptors including CXCR3. The increased Tph cells exhibited “B cell help” signatures similar to that of circulating T follicular helper (cTfh) cells and promoted B cell differentiation in vitro. Compared with cTfh cells, Tph cells produced more IFNγ, inducing tissue-homing chemokine receptors on plasmablasts. Finally, expansion of activated Tph cells was correlated with the frequency of CXCR3+ plasmablasts in the acute phase of patients with stable disease. Our results demonstrate a novel role for Tph cells in acute viral immunity by inducing ectopic, antibody secreting plasmablasts.
“…The mechanisms proposed for anti-TNF ability to increase T regs function are through FoxP3 mRNA and protein up-regulation and restoration of suppressive function through TNF receptor 2 on T regs [38]. Anti-TNF ability to induce LAG-3 on CD4 T cells could result from the observation of its ability to induce the IFN type I pathway [39] and the latter to regulate LAG-3 on T cells [40]. In addition, this study confirmed that sera LAG-3 levels were lower in PsA patients naive to biological treatment compared to healthy controls.…”
Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with T cell dysregulation. The lymphocyte-activation gene (LAG)-3 is one of the regulatory receptors expressed on T cells in a soluble form. LAG-3 expression on T cells was analyzed in vitro in PsA patients with minimal disease activity (MDA), active disease (non-MDA) and healthy controls. In cultured in-vitro peripheral blood mononuclear cells (PBMCs), LAG-3 expression on CD4 + T cells was similar in both MDA PsA patients (7.5 ± 0.9) (n = 14) and healthy controls (7.8 ± 0.6) (n = 15), but significantly lower in non-MDA PsA patients (3.1 ± 0.3) (n = 13) (p < 0.0001). An inverse correlation between PsA clinical disease activity and %CD4 + LAG-3 + T cells in vitro was observed (composite psoriatic disease activity index r = −0.47, p < 0.02 and psoriatic arthritis disease activity score, r = −0.51, p < 0.008). In-vitro co-culture of CD4 + T cells with anti-tumor necrosis factor (TNF) or anti-interleukin (IL)-17A had no effect on LAG-3 + expression in MDA PsA patients and healthy controls. In non-MDA patients,anti-TNF, but not anti-IL-17A, restored the %CD4 + LAG-3 + T cells (7.9 ± 0.9 and 3.2 ± 0.4, respectively) (p < 0.0004). Lower soluble LAG-3 levels were found in sera of naive to biological PsA patients (n = 39) compared to healthy controls (n = 35) (p < 0.03). Impaired LAG-3 on CD4 + T cells may reflect active PsA disease state.Anti-TNFs have potency to up-regulate the CD4 + LAG-3 + T cells in vitro.
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