Identification of Human Antigen‐Specific T Cells Using <scp>MHC</scp> Class I and Class II Tetramers

Krueger, Lori A.; Nugent, Courtney; Hampl, Johannes

doi:10.1002/0471142956.cy0618s30

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…We sensitized B6 females with 2W-OVA.BALB/c (H-2 d ) skins and then mated them with 2W-OVA.BALB/c (H-2 d ) males (Fig 1c). OVA-specific CD8 + T cells were identified by flow cytometry using double fluorophore-labeled OVA:K b tetramers; henceforth, these fetus-and graft-specific T cells are referred to as TFGS (26,27). We note that OVA expressed by the skin or F1 fetus is crosspresented by recipient/dam APCs, although it is possible that maternal APCs are cross-decorated with OVA:K b complexes from F1 cells, or that microchimeric fetal cells are presenting OVA:K b to maternal T cells (7,28).…”

Section: Pregnancy Induces the Expression Of Co-inhibitory Molecules ...mentioning

confidence: 99%

Pregnancy dedifferentiates memory CD8+ T cells into hypofunctional cells with exhaustion-enriched programs

Pollard,

Hynes,

Yin

et al. 2024

JCI Insight

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Alloreactive memory, unlike naïve, CD8 + T cells resist transplantation tolerance protocols and are a critical barrier to long-term graft acceptance in the clinic. We here show that semi-allogeneic pregnancy successfully reprogrammed memory fetus/graft-specific CD8 + T cells (TFGS) towards hypofunction. Female C57BL/6 mice harboring memory CD8 + T cells generated by the rejection of BALB/c skin grafts and then mated with BALB/c males achieved rates of pregnancy comparable to naive controls. Post-partum fetus/graft-specific CD8 + T cells (TFGS) from skin-sensitized dams upregulated expression of T cell exhaustion (TEX) markers (Tox, Eomes, PD-1, TIGIT, and Lag3). Transcriptional analysis corroborated an enrichment of canonical T exhaustion (TEX) genes in post-partum memory TFGS and additionally, revealed a downregulation of a subset of memory-associated transcripts. Strikingly, pregnancy induced extensive epigenetic modifications of exhaustion-and memory-associated genes in memory TFGS, whereas minimal epigenetic modifications were observed in naive TFGS cells. Finally, post-partum memory TFGS durably expressed the exhaustion-enriched phenotype, and their susceptibility to transplantation tolerance was significantly restored compared to memory TFGS. These findings advance the concept of pregnancy as an epigenetic modulator inducing hypofunction in memory CD8 + T cells that has relevance not only for pregnancy and transplantation tolerance, but also for tumor immunity and chronic infections.

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Section: Pregnancy Induces the Expression Of Co-inhibitory Molecules ...mentioning

confidence: 99%

Pregnancy dedifferentiates memory CD8+ T cells into hypofunctional cells with exhaustion-enriched programs

Pollard,

Hynes,

Yin

et al. 2024

JCI Insight

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“…To test whether semi-allogeneic pregnancy is possible in females harboring immunological memory to paternal antigens, we sensitized female C57Bl/6 (B6, H-2 b ) mice with male 2W-OVA.BALB/c (H-2 d ) skin transplantation (skinTx). Donor 2W-OVA.BALB/c mice constitutively express 2W-OVA, a recombinant model antigen, allowing endogenous OVA-specific CD8 + T cells from the recipient to be tracked via flow cytometry using fluorophore-labeled OVA:K b tetramers 18,19 . Recipient B6 mice rejected skin grafts within 10 days (data not shown), and at day 30+ post-transplantation, skin-sensitized females were mated with 2W-OVA.BALB/c males (Sensitized+Pregnancy) (Fig.…”

Section: Pregnancy Induces a Dysfunctional Phenotype In Memory Tfgsmentioning

confidence: 99%

Pregnancy programs epigenetic and transcriptional exhaustion in memory CD8+ T cells

Chong

Pollard

Hynes

et al. 2023

Preprint

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Alloreactive memory T cells, unlike naive T cells, fail to be restrained by transplantation tolerance protocols or regulatory T cells, and therefore represent a critical barrier to long-term graft acceptance. Using female mice sensitized by rejection of fully-mismatched paternal skin allografts, we show that subsequent semi-allogeneic pregnancy successfully reprograms memory fetus/graft-specific CD8+ T cells (TFGS) towards hypofunction in a manner that is mechanistically distinct from naive TFGS. Post-partum memory TFGS were durably hypofunctional, exhibiting enhanced susceptibility to transplantation tolerance induction. Furthermore, multi-omics studies revealed that pregnancy induced extensive phenotypic and transcriptional modifications in memory TFGS reminiscent of T cell exhaustion. Strikingly, at loci transcriptionally modified in both naive and memory TFGS during pregnancy, chromatin remodeling was observed exclusively in memory and not naive TFGS. These data reveal a novel link between T cell memory and hypofunction via exhaustion circuits and pregnancy-mediated epigenetic imprinting. This conceptual advance has immediate clinical relevance to pregnancy and transplantation tolerance.

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“…The procedure, little changed since the original report, allows for the identification of T cells of interest on the basis of the binding specificity of their cell surface receptors for particular MHC-peptide complexes (16-18). Studies using MHC class I tetramers have demonstrated that current methods for enumerating Ag-reactive CD8 + T cells vastly underestimate the size of the Ag-specific, virally induced T cell repertoire (17,18).…”

Section: Introductionmentioning

confidence: 99%

Detection of Foreign Antigen-specific CD4⁺Foxp3⁺Regulatory T Cells by MHC Class II Tetramer and Intracellular CD154 Staining

Choi

2013

Immune Netw

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The unrestricted population of CD4+Foxp3+ regulatory T (Treg) cells, which have been known to control the expression of autoimmune diseases and protective immunity to inflammatory reactions, has led to greater appreciation of functional plasticity. Detecting and/or isolating Ag-specific CD4+Foxp3+ Tregs at the single cell level are required to study their function and plasticity. In this study, we established and compared both MHC class II tetramer and intracellular CD154 staining, in order to detect CD4+Foxp3+ Treg specific for foreign Ag in acute and chronic infections with lymphocytic choriomeningitis virus (LCMV). Our results revealed that MHC class II tetramer staining showed a lower detection rate of LCMV GP66-77-specific CD4+ T cells because most of MHC class II tetramers were unbound and unstable when combined staining was performed with intracellular cytokines. In contrast, intracellular CD154 staining was revealed to be easier and simple for detecting LCMV GP66-77-specific CD4+ T cells, compared to MHC class II tetramer staining. Subsequently, we employed intracellular CD154 staining to detect LCMV GP66-77-specific CD4+Foxp3+ Tregs using Foxp3GFP knock-in mouse, and found that LCMV GP66-77-specific CD4+Foxp3+ Tregs and polyclonal CD4+Foxp3+ Tregs showed differential expansion in mice infected with LCMV Arms or Cl13 at acute (8 and 13 days pi) and chronic phases (35 days pi). Therefore, our results provide insight into the valuable use of intracellular CD154 staining to detect and characterize foreign Ag-specific CD4+Foxp3+ Treg in various models.

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Identification of Human Antigen‐Specific T Cells Using MHC Class I and Class II Tetramers

Cited by 4 publications

References 19 publications

Pregnancy dedifferentiates memory CD8+ T cells into hypofunctional cells with exhaustion-enriched programs

Pregnancy dedifferentiates memory CD8+ T cells into hypofunctional cells with exhaustion-enriched programs

Pregnancy programs epigenetic and transcriptional exhaustion in memory CD8+ T cells

Detection of Foreign Antigen-specific CD4⁺Foxp3⁺Regulatory T Cells by MHC Class II Tetramer and Intracellular CD154 Staining

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Identification of Human Antigen‐Specific T Cells Using MHC Class I and Class II Tetramers

Cited by 4 publications

References 19 publications

Pregnancy dedifferentiates memory CD8+ T cells into hypofunctional cells with exhaustion-enriched programs

Pregnancy dedifferentiates memory CD8+ T cells into hypofunctional cells with exhaustion-enriched programs

Pregnancy programs epigenetic and transcriptional exhaustion in memory CD8+ T cells

Detection of Foreign Antigen-specific CD4+Foxp3+Regulatory T Cells by MHC Class II Tetramer and Intracellular CD154 Staining

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Detection of Foreign Antigen-specific CD4⁺Foxp3⁺Regulatory T Cells by MHC Class II Tetramer and Intracellular CD154 Staining