Dimorphism in the T-cell receptor constant region affects T-cell function, phenotype and HIV outcome

Kaewpreedee, Prathanporn; Boonrat, Potchara; Tansiri, Yada; Rowland‐Jones, Sarah; Hansasuta, Pokrath

doi:10.1097/qad.0000000000002187

Cited by 3 publications

(3 citation statements)

References 31 publications

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“…Other approaches, such as the TRBC1-CAR, are more selective; however, they still deplete a large component of the T-cell repertoire. 32 , 36 We sought to determine whether redundancy in the T-cell repertoire would maintain an immune response against common viruses (CMV, EBV, and influenza virus) after a single TCRvβ family was depleted. T cells from 3 healthy donors depleted of populations belonging to TCRvβ5.1, 9, or 12 were exposed to viral peptides and analyzed for IFN-γ production ( Figure 2 E; supplemental Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“… 24 , 29 , 30 Others have explored the possibility of targeting 1 of 2 constant regions of the TRBC1, 31 but this approach leads to the elimination of half of the healthy T-cell repertoire. Because TRBC1 and TRBC2 T-cell populations differ in their differentiation status, 32 this approach may also impede sufficient immune health. Alternatively, another group reported the ability to develop personalized CARs against the TCR complementarity-determining region 3.…”

Section: Introductionmentioning

confidence: 99%

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TCRvβ-CART therapy mediates high-precision targeting of malignant T-cell clones

Shaw

Poussin

Rodríguez³

et al. 2023

Blood Advances

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Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid malignancies associated with poor prognosis due to ineffective treatment options and high rates of relapse. The success of chimeric antigen receptor T-cell (CART) therapy for certain hematological malignancies makes it an attractive treatment option for PTCLs. However, shared expression of potential target antigens by both malignant and healthy T cells poses a challenge. Current prospective CART approaches cause a high degree of on-target, off-tumor activity, resulting in fratricide during CAR T-cell expansion, depletion of healthy T cells in vivo, and immune compromise in the patient. To limit off-tumor targeting, we sought to develop a CART platform specific for a given TCRvb family that would endow CAR-modified T cells with the ability to mediate lysis of the clonal malignant population while preserving the majority of healthy T cells. Here, CAR constructs specific for multiple TCRvb family members were designed and validated. Our results demonstrate that TCRvb family-specific CAR T cells (TCRvb-CARTs) recognize and kill TCRvb-expressing target cells. This includes specific self-depletion of the targeted cell subpopulation in the CART product and lysis of cell lines engineered to express a target TCRvb family. Furthermore, TCRvb-CARTs eliminated the dominant malignant TCRvb clone in two patient samples. Finally, in immunodeficient mice, TCRvb-CARTs eradicated malignant cells in a TCRvb-dependent manner. Importantly, in all cases the non-targeted TCRvb families were spared. Thus, TCRvb-CART therapy provides a potential option for high-precision treatment of PTCL with limited healthy T-cell depletion.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TCRvβ-CART therapy mediates high-precision targeting of malignant T-cell clones

Shaw

Poussin

Rodríguez³

et al. 2023

Blood Advances

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“…Recently, a single antibody (TRBC1-binding monoclonal antibody, clone JOVI−1) against one of the two mutually exclusive TCR β chain constant domains (TRBC1 and TRBC2) randomly selected during rearrangement of the TRB gene, has been proposed as a potential marker for rapid assessment of Tαβ-cell clonality by FCM [18]. Normal, as well as virus-specific Tαβ-cells, show an admixture of TRBC1-positive (37-51% and 36-52% of normal CD4 + and CD8 + T-cells, respectively) [18][19][20][21][22] and TRBC1-negative (presumably TRBC2 positive) T-cells (polyclonal profile in GeneScan studies), whereas monoclonal Tαβ-cells typically showed restricted (monotypic) TRBC1 expression [18][19][20][21][23][24][25]. Recent reports have further shown the potential utility of this antibody reagent for routine assessment of Tαβ-cell clonality in T-CLPD vs. normal/reactive conditions [18][19][20][21][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Anti-TRBC1 Antibody-Based Flow Cytometric Detection of T-Cell Clonality: Standardization of Sample Preparation and Diagnostic Implementation

Muñoz-García

Lima

Villamor

et al. 2021

Cancers

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A single antibody (anti-TRBC1; JOVI-1 antibody clone) against one of the two mutually exclusive T-cell receptor β-chain constant domains was identified as a potentially useful flow-cytometry (FCM) marker to assess Tαβ-cell clonality. We optimized the TRBC1-FCM approach for detecting clonal Tαβ-cells and validated the method in 211 normal, reactive and pathological samples. TRBC1 labeling significantly improved in the presence of CD3. Purified TRBC1+ and TRBC1− monoclonal and polyclonal Tαβ-cells rearranged TRBJ1 in 44/47 (94%) and TRBJ1+TRBJ2 in 48 of 48 (100%) populations, respectively, which confirmed the high specificity of this assay. Additionally, TRBC1+/TRBC1− ratios within different Tαβ-cell subsets are provided as reference for polyclonal cells, among which a bimodal pattern of TRBC1-expression profile was found for all TCRVβ families, whereas highly-variable TRBC1+/TRBC1− ratios were observed in more mature vs. naïve Tαβ-cell subsets (vs. total T-cells). In 112/117 (96%) samples containing clonal Tαβ-cells in which the approach was validated, monotypic expression of TRBC1 was confirmed. Dilutional experiments showed a level of detection for detecting clonal Tαβ-cells of ≤10−4 in seven out of eight pathological samples. These results support implementation of the optimized TRBC1-FCM approach as a fast, specific and accurate method for assessing T-cell clonality in diagnostic-FCM panels, and for minimal (residual) disease detection in mature Tαβ+ leukemia/lymphoma patients.

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