Human cytomegalovirus expands a CD8
            <sup>+</sup>
            T cell population with loss of
            <i>BCL11B</i>
            expression and gain of NK cell identity

Sottile, Rosa; Panjwani, M. Kazim; Lau, Colleen M.; Daniyan, Anthony F.; Tanaka, Kento; Barker, Juliet N.; Brentjens, Renier J.; Sun, Joseph C.; Luduec, Jean-Benoît Le; Hsu, Katharine C.

doi:10.1126/sciimmunol.abe6968

Cited by 28 publications

(32 citation statements)

References 70 publications

(90 reference statements)

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“…This finding is strengthened by the observation that these cytotoxic lymphocytes did not increase in NV patients. The frequency of NKG2C + T cells is reported to be high in CMV-seropositive healthy donors and hematopoietic stem cell transplant patients who experienced CMV reactivation ( 18 , 30 ). As NKG2C + T cells have the capacity to proliferate in response to different pathogens ( 31 ), CMV is one of the pathogens that can drive an expansion of NKG2C + T cells.…”

Section: Discussionmentioning

confidence: 99%

Mass cytometry reveals single-cell kinetics of cytotoxic lymphocyte evolution in CMV-infected renal transplant patients

Ishiyama

Arakawa-Hoyt

Aguilar

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Cytomegalovirus (CMV) infection is associated with graft rejection in renal transplantation. Memory-like natural killer (NK) cells expressing NKG2C and lacking FcεRIγ are established during CMV infection. Additionally, CD8+ T cells expressing NKG2C have been observed in some CMV-seropositive patients. However, in vivo kinetics detailing the development and differentiation of these lymphocyte subsets during CMV infection remain limited. Here, we interrogated the in vivo kinetics of lymphocytes in CMV-infected renal transplant patients using longitudinal samples compared with those of nonviremic (NV) patients. Recipient CMV-seropositive (R+) patients had preexisting memory-like NK cells (NKG2C+CD57+FcεRIγ–) at baseline, which decreased in the periphery immediately after transplantation in both viremic and NV patients. We identified a subset of prememory-like NK cells (NKG2C+CD57+FcεRIγlow–dim) that increased during viremia in R+ viremic patients. These cells showed a higher cytotoxic profile than preexisting memory-like NK cells with transient up-regulation of FcεRIγ and Ki67 expression at the acute phase, with the subsequent accumulation of new memory-like NK cells at later phases of viremia. Furthermore, cytotoxic NKG2C+CD8+ T cells and γδ T cells significantly increased in viremic patients but not in NV patients. These three different cytotoxic cells combinatorially responded to viremia, showing a relatively early response in R+ viremic patients compared with recipient CMV-seronegative viremic patients. All viremic patients, except one, overcame viremia and did not experience graft rejection. These data provide insights into the in vivo dynamics and interplay of cytotoxic lymphocytes responding to CMV viremia, which are potentially linked with control of CMV viremia to prevent graft rejection.

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Section: Discussionmentioning

confidence: 99%

Mass cytometry reveals single-cell kinetics of cytotoxic lymphocyte evolution in CMV-infected renal transplant patients

Ishiyama

Arakawa-Hoyt

Aguilar

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…A paper by Sottile and colleagues demonstrated that similar to NK cells, NKG2C+ is expressed by CD8+ T cells, is associated with HCMV exposure, resides at the boundary between innate and adaptive immunity and exhibited strong effector function against HCMV-infected fibroblasts [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of NKG2-A/-C, Kir and CD57 on NK Cells Stimulated with pp65 and IE-1 Antigens in Patients Awaiting Lung Transplant

Bergantini

d’Alessandro

Otranto

et al. 2022

Life

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Introduction: Cytomegalovirus (CMV) is the leading opportunistic infection in lung transplant (LTx) recipients. CMV is associated with graft failure and decreased survival. Recently, new antiviral therapies have been proposed. The present study aimed to investigate NK and T cell subsets of patients awaiting LTx. We analyzed the cellular populations between reactive and non-reactive QuantiFERON (QF) CMV patients for the prediction of immunological response to infection. Methods: Seventeen pre-LTx patients and 15 healthy controls (HC) have been enrolled. QF and IFN-γ ELISA assay detections were applied. NK cell subsets and T cell and proliferation assay were detected before and after stimulation with pp-65 and IE-1 CMV antigens after stratification as QF+ and QF−. Furthermore, we quantified the serum concentrations of NK− and T-related cytokines by bead-based multiplex analysis. Results: CD56brCD16lowNKG2A+KIR+ resulted in the best discriminatory cellular subsets between pre-LTx and HC. Discrepancies emerged between serology and QF assay. Better proliferative capability emerged from patients who were QF+, in particular in CD8 and CD25-activated cells. CD56brCD16low, adaptive/memory-like NK and CD8Teff were highly increased only in QF+ patients. Conclusions: QF more than serology is useful in the detection of patients able to respond to viral infection. This study provides new insights in terms of immunological responses to CMV in pre-LTX patients, particularly in NK and T cells biology.

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“…To reveal the conserved regulatory code across organisms, we also constructed the regulatory networks in matched human immune cells using Taiji framework. The systematic comparison of constitutively active TFs and cell lineage-specific TFs showed that some TFs undertake similar crucial roles in the development and differentiation of immune cells in both human and mouse systems, like Stat1, Stat3 [107][108][109], Sp2 and Sp3 [110][111][112] as common constitutively active TFs; Eomes [86][87][88], Bcl11b [89][90][91], Lef1 and Tcf7 [27,92,93] as CD4 + and CD8 + T-important TFs. This systematic analysis that spans all the immune cell lineages identifies the conserved TFs across species and shows the potential of elucidating the molecular functions of unknown TFs in human immune system.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the overlap percentages for CD4 + and CD8 + T cells are relatively small, 11% and 14%, respectively. The conserved TFs like Eomes [86][87][88], Bcl11b [89][90][91], Lef1 and Tcf7 [27,92,93] are well-known for their important roles in T cell differentiation in both systems. We also identified species-specific TFs including Msc, Maz, Klf5 and Snai3, Sp4, and Foxo4 in human and mouse CD8 + T cells, respectively.…”

Section: Systematic Comparison Between Human and Mouse Immune Cells R...mentioning

confidence: 99%

Systems-level identification of key transcription factors in immune cell specification

Liu

Omilusik

Toma

et al. 2022

Preprint

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SummaryTranscription factors (TFs) are crucial for regulating cell differentiation during the development of the immune system. However, the key TFs for orchestrating the specification of distinct immune cells are not fully understood. Here, we integrated the transcriptomic and epigenomic measurements in 73 mouse and 61 human primary cell types, respectively, that span the immune cell differentiation pathways. We constructed the cell-type-specific transcriptional regulatory network and assessed the global importance of TFs based on the Taiji framework, which is a method we have previously developed that can infer the global impact of TFs using integrated transcriptomic and epigenetic data. Integrative analysis across cell types revealed putative driver TFs in cell lineage-specific differentiation in both mouse and human systems. We have also identified TF combinations that play important roles in specific developmental stages. Furthermore, we validated the functions of predicted novel TFs in murine CD8+ T cell differentiation and showed the importance of Elf1 and Prdm9 in the effector versus memory T cell fate specification and Kdm2b and Tet3 in promoting differentiation of CD8+ tissue resident memory (Trm) cells, validating the approach. Thus, we have developed a bioinformatic approach that provides a global picture of the regulatory mechanisms that govern cellular differentiation in the immune system and aids the discovery of novel mechanisms in cell fate decisions.

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Human cytomegalovirus expands a CD8 ⁺ T cell population with loss of BCL11B expression and gain of NK cell identity

Abstract: NKG2C + CD8 + T cells, found in 40% of HCMV-seropositive individuals, have lost BCL11B expression and adopt an innate-like identity.

Cited by 28 publications

References 70 publications

Mass cytometry reveals single-cell kinetics of cytotoxic lymphocyte evolution in CMV-infected renal transplant patients

Mass cytometry reveals single-cell kinetics of cytotoxic lymphocyte evolution in CMV-infected renal transplant patients

Characterization of NKG2-A/-C, Kir and CD57 on NK Cells Stimulated with pp65 and IE-1 Antigens in Patients Awaiting Lung Transplant

Systems-level identification of key transcription factors in immune cell specification

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Human cytomegalovirus expands a CD8 + T cell population with loss of BCL11B expression and gain of NK cell identity

Abstract: NKG2C + CD8 + T cells, found in 40% of HCMV-seropositive individuals, have lost BCL11B expression and adopt an innate-like identity.

Cited by 28 publications

References 70 publications

Mass cytometry reveals single-cell kinetics of cytotoxic lymphocyte evolution in CMV-infected renal transplant patients

Mass cytometry reveals single-cell kinetics of cytotoxic lymphocyte evolution in CMV-infected renal transplant patients

Characterization of NKG2-A/-C, Kir and CD57 on NK Cells Stimulated with pp65 and IE-1 Antigens in Patients Awaiting Lung Transplant

Systems-level identification of key transcription factors in immune cell specification

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Human cytomegalovirus expands a CD8 ⁺ T cell population with loss of BCL11B expression and gain of NK cell identity