Quantifying size and diversity of the human T cell alloresponse

DeWolf, Susan; Grinshpun, Boris; Savage, Thomas; Lau, Sai Ping; Obradovic, Aleksandar Z.; Shonts, Brittany; Yang, Sherry; Morris, Heather; Zuber, Julien; Winchester, Robert; Sykes, Megan; Shen, Yufeng

doi:10.1172/jci.insight.121256

Cited by 71 publications

(99 citation statements)

References 47 publications

(61 reference statements)

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“…15 Clinical information on the 8 subjects studied is summarized in Tables S1 and S2; all 8 subjects studied were randomized to immunosuppression withdrawal. 16,17 We applied minimum frequency and fold change criteria in identifying the donor-reactive TCRβ sequences to avoid including FACS contaminants and high frequency but not donor-specific T cells undergoing bystander proliferation in this dataset. 16,17 We applied minimum frequency and fold change criteria in identifying the donor-reactive TCRβ sequences to avoid including FACS contaminants and high frequency but not donor-specific T cells undergoing bystander proliferation in this dataset.…”

Section: Reduced Detection Of Donor-reactive T Cell Tcrβ Sequences mentioning

confidence: 99%

“…We identified donorreactive clones via the pretransplant CFSE-MLR as unique TCRβ sequences with frequency ≥0.01% in the CFSE lo sample that were at least 5-fold expanded in the CFSE lo sample relative to the pretransplant unstimulated sample as described and validated previously ( Figure 1B). 16,17 We applied minimum frequency and fold change criteria in identifying the donor-reactive TCRβ sequences to avoid including FACS contaminants and high frequency but not donor-specific T cells undergoing bystander proliferation in this dataset.…”

Section: Reduced Detection Of Donor-reactive T Cell Tcrβ Sequences mentioning

confidence: 99%

“…The Immune Tolerance Network (ITN)-sponsored clinical trial ITN030ST ("A-WISH") randomized liver transplant recipients, stratified as HCV infected and not, to begin weaning immunosuppression within 1 to 2 years posttransplant, aiming for complete withdrawal. 16,17 The method involves a pretransplant recipient antidonor mixed lymphocyte reaction (MLR) followed by high-throughput TCRβ CDR3 sequencing of proliferating cells. 15 Based on the results of these rodent studies and on an ITNsponsored trial of combined kidney-bone marrow transplant (CKBMT) in which we obtained evidence for long-term clonal deletion of donor-reactive T cells as a mechanism of renal allograft tolerance, 16 we hypothesized that patients defined as tolerant in ITN030ST might demonstrate deletion of donor-reactive T cells in the circulation.…”

mentioning

confidence: 99%

“…We addressed this hypothesis by using a highthroughput TCR sequencing-based method that we developed for identifying and tracking a significant fraction of the alloreactive T cell repertoire in any donor-recipient pair. 16,17 The method involves a pretransplant recipient antidonor mixed lymphocyte reaction (MLR) followed by high-throughput TCRβ CDR3 sequencing of proliferating cells. Individual T cells have 1 or 2 TCR α chains and a single TCR β chain (TCRβ).…”

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confidence: 99%

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Deletion of donor-reactive T cell clones after human liver transplant

Savage

Shonts

Lau

et al. 2020

American Journal of Transplantation

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| INTRODUC TI ONLiver transplantation has been associated with relatively high rates of successful immunosuppression withdrawal in recipients who have been free of rejection for years. 1,2 Despite T cell infiltration associated with hepatitis C virus (HCV) and recurrent HCV posttransplant, 3 a subset of HCV-infected liver transplant recipients have successfully achieved tolerance. 4Spontaneous liver allograft tolerance occurs in rodent models across major histocompatibility complex barriers 5 and is associated with donor-specific tolerance to subsequent skin 6 or cardiac allografts. 7 Moreover, cotransplantation of liver allografts in humans We recently developed a high throughput T cell receptor β chain (TCRβ) sequencing-based approach to identifying and tracking donor-reactive T cells. To address the role of clonal deletion in liver allograft tolerance, we applied this method in samples from a recent randomized study, ITN030ST, in which immunosuppression withdrawal was attempted within 2 years of liver transplantation. We identified donor-reactive T cell clones via TCRβ sequencing following a pre-transplant mixed lymphocyte reaction and tracked these clones in the circulation following transplantation in 3 tolerant and 5 non-tolerant subjects. All subjects showed a downward trend and significant reductions in donor-reactive TCRβ sequences were detected post-transplant in 6 of 8 subjects, including 2 tolerant and 4 non-tolerant recipients. Reductions in donor-reactive TCRβ sequences were greater than those of all other TCRβ sequences, including 3rd party-reactive sequences, in all 8 subjects, demonstrating an impact of the liver allograft after accounting for repertoire turnover. Although limited by patient number and heterogeneity, our results suggest that partial deletion of donor-reactive T cell clones may be a consequence of liver transplantation and does not correlate with success or failure of early immunosuppression withdrawal. These observations underscore the organ-and/or protocol-specific nature of tolerance mechanisms in humans. K E Y W O R D Sbasic (laboratory) research/science, immunobiology, liver transplantation/hepatology, monitoring: immune, T cell biology, tolerance

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Section: Reduced Detection Of Donor-reactive T Cell Tcrβ Sequences mentioning

confidence: 99%

Section: Reduced Detection Of Donor-reactive T Cell Tcrβ Sequences mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Deletion of donor-reactive T cell clones after human liver transplant

Savage

Shonts

Lau

et al. 2020

American Journal of Transplantation

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“…5 (C) and (D). Such flat distributions have been observed in several sequencing experiments [17,[50][51][52] even though Th clone types are discriminated only by the TCR sequences in the experiments. To compare the abundance distributions obtained using our model with the experimental ones, we use the TCR sequences of CD4+ T cells collected from the peripheral blood of two healthy human donors (HV01 and HVD4) reported in [53].…”

Section: Numerical Simulations and Clone Size Distribution Aftermentioning

confidence: 63%

Understanding Adaptive Immune System as Reinforcement Learning

Kato

Kobayashi

2020

Preprint

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The adaptive immune system of vertebrates can detect, respond to, and memorize diverse pathogens from past experience. While the selection of T helper (Th) clones is the simple and established mechanism to recognize and memorize new pathogens, the question that still remains unexplored is how the Th cells can acquire better ways to bias the responses of immune cells for eliminating pathogens more efficiently by translating the recognized antigen information into regulatory signals. In this work, we address this problem by associating the adaptive immune network organized by the Th cells with reinforcement learning (RL). By employing recent advancements of network-based RL, we show that the Th immune network can acquire the association between antigen patterns of and the effective responses to pathogens. Moreover, the clonal selection as well as other inter-cellular interactions are derived as a learning rule of this network. We also demonstrate that the stationary clone-size distribution after learning shares characteristic features with those observed experimentally. Our theoretical framework may contribute to revising and renewing our understanding of adaptive immunity as a learning system.

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T cell activation contributes to purifying selection against the MELAS‐associated m.3243A>G pathogenic variant in blood

Walker,

Li,

Livak

et al. 2024

J of Inher Metab Disea

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T cells have been shown to maintain a lower percentage (heteroplasmy) of the pathogenic m.3243A>G variant (MT‐TL1, associated with maternally inherited diabetes and deafness [MIDD] and mitochondrial encephalomyopathy with lactic acidosis and stroke‐like episodes [MELAS]). The mechanism(s) underlying this purifying selection, however, remain unknown. Here we report that purified patient memory CD4+ T cells have lower bulk m.3243A>G heteroplasmy compared to naïve CD4+ T cells. In vitro activation of naïve CD4+ m.3243A>G patient T cells results in lower bulk m.3243A>G heteroplasmy after proliferation. Finally, m.3243A>G patient T cell receptor repertoire sequencing reveals relative oligoclonality compared to controls. These data support a role for T cell activation in peripheral, purifying selection against high m.3243A>G heteroplasmy T cells at the level of the cell, in a likely cell‐autonomous fashion.

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Quantifying size and diversity of the human T cell alloresponse

Cited by 71 publications

References 47 publications

Deletion of donor-reactive T cell clones after human liver transplant

Deletion of donor-reactive T cell clones after human liver transplant

Understanding Adaptive Immune System as Reinforcement Learning

T cell activation contributes to purifying selection against the MELAS‐associated m.3243A>G pathogenic variant in blood

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