GXMR-CAR containing distinct GXM-specific single-chain variable fragment (scFv) mediated the cell activation against Cryptococcus spp. And had difference in the strength of tonic signaling
Cryptococcus spp. has a polysaccharide capsule composed of glucuronoxylomannan-GXM, a major virulence factor that can prevent the recognition of fungi by immune cells. Chimeric Antigen Receptor (CAR) redirects T cells to target Cryptococcus spp. as previously demonstrated by a CAR specific to GXM, GXMR-CAR. The current study evaluated the strength of the signal transduction triggered by GXMR-CAR, composed of a distinct antigen-binding domain sourced from a single-chain variable fragment (scFv). GXM-specific scFv derived from mAbs 2H1 and 18B7, 2H1-GXMR-CAR and 18B7-GXMR-CAR, respectively, were designed to express CD8 molecule as hinge/transmembrane, and the costimulatory molecule CD137 (4-1BB) coupled to CD3ζ. The 2H1-GXMR-CAR or 18B7-GXMR-CAR Jurkat cells recognized soluble GXM from C. gattii and C. neoformans, and the levels of IL-2 released by the modified cells did not differ between the GXMR-CAR constructs after exposure to Cryptococcus spp. 18B7-GXMR-CAR triggered tonic signaling was more pronounced in modified Jurkat cells, and a protein kinase inhibitor of the Src family (dasatinib) significantly reduced GXMR-CAR tonic signaling and inhibited cell activation against ligands. 18B7 scFv showed a structural modification of the variable heavy (VH) chain that clarified the difference in the strength of tonic signaling and the level of cell activation between 2H1-GXMR-CAR and 18B7-GXMR-CAR. GXMR-CAR constructs induced T-cell activation against clinical isolates of Cryptococcus spp. and serum from patients with cryptococcosis induced high levels of IL-2, mainly in cells modified with 18B7-GXMR-CAR. Thus, 18B7-GXMR-CAR and 2H1-GXMR-CAR mediated T cell activation against Cryptococcus spp. and 18B7 and 2H1 scFv influenced the strength of tonic signaling.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2023 |
---|---|
Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
---|---|
Enthalten in: |
Bioengineered - 14(2023), 1 vom: 17. Dez., Seite 2281059 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Machado, Michele Procópio [VerfasserIn] |
---|
Links: |
---|
Themen: |
Chimeric antigen receptor |
---|
Anmerkungen: |
Date Completed 20.11.2023 Date Revised 04.01.2024 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1080/21655979.2023.2281059 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM364703717 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM364703717 | ||
003 | DE-627 | ||
005 | 20240108141705.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2023 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1080/21655979.2023.2281059 |2 doi | |
028 | 5 | 2 | |a pubmed24n1248.xml |
035 | |a (DE-627)NLM364703717 | ||
035 | |a (NLM)37978838 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Machado, Michele Procópio |e verfasserin |4 aut | |
245 | 1 | 0 | |a GXMR-CAR containing distinct GXM-specific single-chain variable fragment (scFv) mediated the cell activation against Cryptococcus spp. And had difference in the strength of tonic signaling |
264 | 1 | |c 2023 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 20.11.2023 | ||
500 | |a Date Revised 04.01.2024 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Cryptococcus spp. has a polysaccharide capsule composed of glucuronoxylomannan-GXM, a major virulence factor that can prevent the recognition of fungi by immune cells. Chimeric Antigen Receptor (CAR) redirects T cells to target Cryptococcus spp. as previously demonstrated by a CAR specific to GXM, GXMR-CAR. The current study evaluated the strength of the signal transduction triggered by GXMR-CAR, composed of a distinct antigen-binding domain sourced from a single-chain variable fragment (scFv). GXM-specific scFv derived from mAbs 2H1 and 18B7, 2H1-GXMR-CAR and 18B7-GXMR-CAR, respectively, were designed to express CD8 molecule as hinge/transmembrane, and the costimulatory molecule CD137 (4-1BB) coupled to CD3ζ. The 2H1-GXMR-CAR or 18B7-GXMR-CAR Jurkat cells recognized soluble GXM from C. gattii and C. neoformans, and the levels of IL-2 released by the modified cells did not differ between the GXMR-CAR constructs after exposure to Cryptococcus spp. 18B7-GXMR-CAR triggered tonic signaling was more pronounced in modified Jurkat cells, and a protein kinase inhibitor of the Src family (dasatinib) significantly reduced GXMR-CAR tonic signaling and inhibited cell activation against ligands. 18B7 scFv showed a structural modification of the variable heavy (VH) chain that clarified the difference in the strength of tonic signaling and the level of cell activation between 2H1-GXMR-CAR and 18B7-GXMR-CAR. GXMR-CAR constructs induced T-cell activation against clinical isolates of Cryptococcus spp. and serum from patients with cryptococcosis induced high levels of IL-2, mainly in cells modified with 18B7-GXMR-CAR. Thus, 18B7-GXMR-CAR and 2H1-GXMR-CAR mediated T cell activation against Cryptococcus spp. and 18B7 and 2H1 scFv influenced the strength of tonic signaling | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Chimeric antigen receptor | |
650 | 4 | |a GXM | |
650 | 4 | |a T cells | |
650 | 4 | |a cryptococcus spp | |
650 | 4 | |a tonic signaling | |
650 | 7 | |a Single-Chain Antibodies |2 NLM | |
650 | 7 | |a Receptors, Chimeric Antigen |2 NLM | |
650 | 7 | |a Interleukin-2 |2 NLM | |
650 | 7 | |a Polysaccharides |2 NLM | |
700 | 1 | |a Dos Santos, Matheus Henrique |e verfasserin |4 aut | |
700 | 1 | |a Guimarães, Júlia Garcia |e verfasserin |4 aut | |
700 | 1 | |a de Campos, Gabriela Yamazaki |e verfasserin |4 aut | |
700 | 1 | |a Oliveira Brito, Patrícia Kellen Martins |e verfasserin |4 aut | |
700 | 1 | |a Ferreira, Camilly Melo Garcia |e verfasserin |4 aut | |
700 | 1 | |a Rezende, Caroline Patini |e verfasserin |4 aut | |
700 | 1 | |a Frota, Natália Fernandes |e verfasserin |4 aut | |
700 | 1 | |a Soares, Sandro Gomes |e verfasserin |4 aut | |
700 | 1 | |a Kumaresan, Pappanaicken R |e verfasserin |4 aut | |
700 | 1 | |a Lourenzoni, Marcos Roberto |e verfasserin |4 aut | |
700 | 1 | |a da Silva, Thiago Aparecido |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Bioengineered |d 2012 |g 14(2023), 1 vom: 17. Dez., Seite 2281059 |w (DE-627)NLM218688679 |x 2165-5987 |7 nnns |
773 | 1 | 8 | |g volume:14 |g year:2023 |g number:1 |g day:17 |g month:12 |g pages:2281059 |
856 | 4 | 0 | |u http://dx.doi.org/10.1080/21655979.2023.2281059 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 14 |j 2023 |e 1 |b 17 |c 12 |h 2281059 |