Toll-like receptor 5 deficiency protects from wasting disease in a T cell transfer colitis model in T cell receptor-β-deficient mice

Abstract Abstract 4226 Several studies have demonstrated the clinical efficacy of adoptive T cell therapy for targeting cancer. Using HLA-A2.1 transgenic mice, we have demonstrated the feasibility of T-cell receptor (TCR) gene transfer into T cells to circumvent self-tolerance to the widely expressed human p53(264–272) tumor-associated antigen and developed approaches to generate high-affinity CD8-independent TCR. A safety concern of TCR gene transfer is the pairing of endogenous and introduced TCR chains resulting in the potential generation of self-reactive T cells (off-target autoimmunity). Several strategies to favor matched TCR chains pairing and thus enhancing TCR cell surface expression, including optimization of TCR encoding nucleotide sequences, introduction of an additional inter-chain disulfide bond between the TCR α and β chain constant domains, coexpression of both TCR α and β encoding-genes using self-cleaving 2A virus peptide-based retroviral vectors have been applied. However, adoptive transfer of mouse T cells transduced with modified p53-specific TCRs into p53-deficient humanized (A2Kb) mice was inducing lethal autoimmunity due to the formation of self-reactive TCRs infiltrating vital organs, such as spleen, liver and bone marrow. Therefore, an optimized single chain (sc) p53-specific TCR was engineered to avoid the formation of mismatched TCR heterodimers. The safety and therapeutic efficiency of this approach were evaluated in humanized mouse models of adoptive T cell transfer and successfully demonstrated that optimized p53-specific scTCR-redirected T cells (i) do not induce OFF-target autoimmunity and (ii) mediate antitumor reactivity. Importantly, because the expression of p53 antigen on normal tissues raises the concern of potential on-target toxicity, we performed adoptive T cell transfer experiments in humanized mice expressing the Human p53 protein (Hupki mice) and did not observe any sign of TCR gene transfer-mediated GvHD in this model. In conclusion, these mouse studies suggest that the optimized p53(264–272)-specific scTCR could represent a safe and efficient approach for TCR-based gene therapy. Disclosures: No relevant conflicts of interest to declare.

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T cell-induced inflammation of the small and large intestine in immunodeficient mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00214.2005 ◽

2006 ◽

Vol 290 (1) ◽

pp. G109-G119 ◽

Cited By ~ 55

Author(s):

Dmitry V. Ostanin ◽

Kevin P. Pavlick ◽

Sulaiman Bharwani ◽

Dwain D′Souza ◽

Kathryn L. Furr ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Small Bowel ◽

T Cell Receptor ◽

Cell Receptor ◽

Cell Transfer ◽

Chronic Colitis ◽

Naive T Cells ◽

Naïve T Cells ◽

T Cell Transfer

It is well known that transfer of CD4+CD45RBhigh (naïve) T cells into syngeneic lymphocyte-deficient mice induces chronic colitis. However, no studies have reported the presence of small bowel inflammation in this T cell-dependent model. Therefore, the objective of this study was to evaluate and compare small and large bowel inflammation induced by transfer of naïve T cells into two different immunodeficient recipient mice. T and B cell-deficient recombinase activating gene 1-deficient [RAG knockout (KO)] and T cell-deficient T cell receptor-β × T cell receptor-δ double-deficient (TCR KO) mice were reconstituted with wild-type naïve T cells and observed for signs of disease. We found that reconstituted RAG KO mice developed moderate to severe colitis and inflammation of the entire small intestine at 6–8 wk after T cell transfer. Adoptive transfer of naïve T cells into TCR KO mice induced a milder form of chronic colitis and small bowel inflammation that was confined primarily to the duodenum at 10–12 wk after T cell transfer. T helper cell 1 and macrophage-derived proinflammatory cytokine mRNA levels correlated well with the localization and severity of the chronic large and small bowel inflammation. In addition, we observed comparable homing and expansion of donor lymphocytes in the gut and secondary lymphoid tissues of both recipients. Taken together, our data demonstrate that transfer of naïve T cells into immunodeficient recipient mice induces both chronic small and large bowel inflammation and that the presence of B cells in the TCR KO recipients may play a role in regulating chronic intestinal inflammation.

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Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0708426104 ◽

2007 ◽

Vol 104 (43) ◽

pp. 17034-17039 ◽

Cited By ~ 196

Author(s):

H. G. Evans ◽

T. Suddason ◽

I. Jackson ◽

L. S. Taams ◽

G. M. Lord

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Toll Like Receptor ◽

T Helper ◽

T Helper 17 ◽

T Helper 17 Cells ◽

Activated Monocytes ◽

Receptor Ligation

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Abstract 6590: Epigenetic suppression of transgenic T-cell receptor (TCR) expression in adoptive cell transfer (ACT) therapy

10.1158/1538-7445.am2020-6590 ◽

2020 ◽

Author(s):

Theodore S. Nowicki ◽

Colin Farrell ◽

Marco Morselli ◽

Liudmilla Rubbi ◽

Katie Campbell ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Adoptive Cell Transfer ◽

Cell Transfer ◽

Epigenetic Suppression

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Role of CD137 (4-1BB) in the SCID T cell transfer colitis model

Gastroenterology ◽

10.1016/s0016-5085(03)81678-5 ◽

2003 ◽

Vol 124 (4) ◽

pp. A333

Author(s):

Philippe Maerten ◽

Chong Shen ◽

Pascal Cadot ◽

Gert Van assche ◽

Karel Geboes ◽

...

Keyword(s):

T Cell ◽

Cell Transfer ◽

T Cell Transfer ◽

Colitis Model

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The CD3-γδε and CD3-ζ/η Modules Are Each Essential for Allelic Exclusion at the T Cell Receptor β Locus but Are Both Dispensable for the Initiation of V to (D)J Recombination at the T Cell Receptor–β, –γ, and –δ Loci

Journal of Experimental Medicine ◽

10.1084/jem.187.1.105 ◽

1998 ◽

Vol 187 (1) ◽

pp. 105-116 ◽

Cited By ~ 35

Author(s):

Laurence Ardouin ◽

Jamila Ismaili ◽

Bernard Malissen ◽

Marie Malissen

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Mutant Mice ◽

Allelic Exclusion ◽

Gene Products ◽

Β Chain ◽

Deficient Mice

The pre–T cell receptor (TCR) associates with CD3-transducing subunits and triggers the selective expansion and maturation of T cell precursors expressing a TCR-β chain. Recent experiments in pre-Tα chain-deficient mice have suggested that the pre-TCR may not be required for signaling allelic exclusion at the TCR-β locus. Using CD3-ε– and CD3-ζ/η–deficient mice harboring a productively rearranged TCR-β transgene, we showed that the CD3-γδε and CD3-ζ/η modules, and by inference the pre-TCR/CD3 complex, are each essential for the establishment of allelic exclusion at the endogenous TCR-β locus. Furthermore, using mutant mice lacking both the CD3-ε and CD3-ζ/η genes, we established that the CD3 gene products are dispensable for the onset of V to (D)J recombination (V, variable; D, diversity; J, joining) at the TCR-β, TCR-γ, and TCR-δ loci. Thus, the CD3 components are differentially involved in the sequential events that make the TCR-β locus first accessible to, and later insulated from, the action of the V(D)J recombinase.

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Pre–T Cell Receptor (Tcr) and Tcr-Controlled Checkpoints in T Cell Differentiation Are Set by Ikaros

Journal of Experimental Medicine ◽

10.1084/jem.190.8.1039 ◽

1999 ◽

Vol 190 (8) ◽

pp. 1039-1048 ◽

Cited By ~ 108

Author(s):

Susan Winandy ◽

Li Wu ◽

Jin-Hong Wang ◽

Katia Georgopoulos

Keyword(s):

Cell Differentiation ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

T Cell Differentiation ◽

Tcr Signaling ◽

Double Positive ◽

Single Positive ◽

T Cell Malignancies ◽

Deficient Mice

T cell differentiation relies on pre–T cell receptor (TCR) and TCR signaling events that take place at successive steps of the pathway. Here, we show that two of these T cell differentiation checkpoints are regulated by Ikaros. In the absence of Ikaros, double negative thymocytes can differentiate to the double positive stage without expression of a pre-TCR complex. Subsequent events in T cell development mediated by TCR involving transition from the double positive to the single positive stage are also regulated by Ikaros. Nonetheless, in Ikaros-deficient thymocytes, the requirement of pre-TCR expression for expansion of immature thymocytes as they progress to the double positive stage is still maintained, and the T cell malignancies that invariably arise in the thymus of Ikaros-deficient mice are dependent on either pre-TCR or TCR signaling. We conclude that Ikaros regulates T cell differentiation, selection, and homeostasis by providing signaling thresholds for pre-TCR and TCR.

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