Concomitant disruption of CD4 and CD8 genes facilitates the development of double negative ab TCR+ peripheral T cells that respond robustly to staphylococcal superantigen

Vaidehi R. Chowdhary, Ashton Krogman, Ashenafi Y. Tilahun, Mariam P Alexander, Chella S. David, Govindarajan Rajagopalan

Research output: Contribution to journalArticle

Abstract

Mature peripheral double negative T (DNT) cells expressing ab TCR but lacking CD4/CD8 coreceptors play protective as well as pathogenic roles. To better understand their development and functioning in vivo, we concomitantly inactivated CD4 and CD8 genes in mice with intact MHC class I and class II molecules with the hypothesis that this would enable the development of DNT cells. We also envisaged that these DNT cells could be activated by bacterial superantigens in vivo as activation of T cells by superantigens does not require CD4 and CD8 coreceptors. Because HLA class II molecules present superantigens more efficiently than murine MHC class II molecules, CD4 CD8 double knockout (DKO) mice transgenically expressing HLA-DR3 or HLA-DQ8 molecules were generated. Although thymic cellularity was comparable between wild type (WT) and DKO mice, CD3+ ab TCR+ thymocytes were significantly reduced in DKO mice, implying defects in thymic-positive selection. Splenic CD3+ ab TCR+ cells and Foxp3+ T regulatory cells were present in DKO mice but significantly reduced. However, the in vivo inflammatory responses and immunopathology elicited by acute challenge with the staphylococcal superantigen enterotoxin B were comparable between WT and DKO mice. Choric exposure to staphylococcal enterotoxin B precipitated a lupus-like inflammatory disease with characteristic lympho-monocytic infiltration in lungs, livers, and kidneys, along with production of anti-nuclear Abs in DKO mice as in WT mice. Overall, our results suggest that DNT cells can develop efficiently in vivo and chronic exposure to bacterial superantigens may precipitate a lupus-like autoimmune disease through activation of DNT cells.

Original languageEnglish (US)
Pages (from-to)4413-4424
Number of pages12
JournalJournal of Immunology
Volume198
Issue number11
DOIs
StatePublished - Jun 1 2017

Fingerprint

Superantigens
Knockout Mice
T-Lymphocytes
Genes
HLA-DR3 Antigen
CD4 Antigens
Regulatory T-Lymphocytes
Thymocytes
Autoimmune Diseases
Kidney
Lung
Liver

ASJC Scopus subject areas

  • Immunology

Cite this

Concomitant disruption of CD4 and CD8 genes facilitates the development of double negative ab TCR+ peripheral T cells that respond robustly to staphylococcal superantigen. / Chowdhary, Vaidehi R.; Krogman, Ashton; Tilahun, Ashenafi Y.; Alexander, Mariam P; David, Chella S.; Rajagopalan, Govindarajan.

In: Journal of Immunology, Vol. 198, No. 11, 01.06.2017, p. 4413-4424.

Research output: Contribution to journalArticle

Chowdhary, Vaidehi R. ; Krogman, Ashton ; Tilahun, Ashenafi Y. ; Alexander, Mariam P ; David, Chella S. ; Rajagopalan, Govindarajan. / Concomitant disruption of CD4 and CD8 genes facilitates the development of double negative ab TCR+ peripheral T cells that respond robustly to staphylococcal superantigen. In: Journal of Immunology. 2017 ; Vol. 198, No. 11. pp. 4413-4424.
@article{18bd3efa39f848a2a93f0b0eaf9432da,
title = "Concomitant disruption of CD4 and CD8 genes facilitates the development of double negative ab TCR+ peripheral T cells that respond robustly to staphylococcal superantigen",
abstract = "Mature peripheral double negative T (DNT) cells expressing ab TCR but lacking CD4/CD8 coreceptors play protective as well as pathogenic roles. To better understand their development and functioning in vivo, we concomitantly inactivated CD4 and CD8 genes in mice with intact MHC class I and class II molecules with the hypothesis that this would enable the development of DNT cells. We also envisaged that these DNT cells could be activated by bacterial superantigens in vivo as activation of T cells by superantigens does not require CD4 and CD8 coreceptors. Because HLA class II molecules present superantigens more efficiently than murine MHC class II molecules, CD4 CD8 double knockout (DKO) mice transgenically expressing HLA-DR3 or HLA-DQ8 molecules were generated. Although thymic cellularity was comparable between wild type (WT) and DKO mice, CD3+ ab TCR+ thymocytes were significantly reduced in DKO mice, implying defects in thymic-positive selection. Splenic CD3+ ab TCR+ cells and Foxp3+ T regulatory cells were present in DKO mice but significantly reduced. However, the in vivo inflammatory responses and immunopathology elicited by acute challenge with the staphylococcal superantigen enterotoxin B were comparable between WT and DKO mice. Choric exposure to staphylococcal enterotoxin B precipitated a lupus-like inflammatory disease with characteristic lympho-monocytic infiltration in lungs, livers, and kidneys, along with production of anti-nuclear Abs in DKO mice as in WT mice. Overall, our results suggest that DNT cells can develop efficiently in vivo and chronic exposure to bacterial superantigens may precipitate a lupus-like autoimmune disease through activation of DNT cells.",
author = "Chowdhary, {Vaidehi R.} and Ashton Krogman and Tilahun, {Ashenafi Y.} and Alexander, {Mariam P} and David, {Chella S.} and Govindarajan Rajagopalan",
year = "2017",
month = "6",
day = "1",
doi = "10.4049/jimmunol.1601991",
language = "English (US)",
volume = "198",
pages = "4413--4424",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "11",

}

TY - JOUR

T1 - Concomitant disruption of CD4 and CD8 genes facilitates the development of double negative ab TCR+ peripheral T cells that respond robustly to staphylococcal superantigen

AU - Chowdhary, Vaidehi R.

AU - Krogman, Ashton

AU - Tilahun, Ashenafi Y.

AU - Alexander, Mariam P

AU - David, Chella S.

AU - Rajagopalan, Govindarajan

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Mature peripheral double negative T (DNT) cells expressing ab TCR but lacking CD4/CD8 coreceptors play protective as well as pathogenic roles. To better understand their development and functioning in vivo, we concomitantly inactivated CD4 and CD8 genes in mice with intact MHC class I and class II molecules with the hypothesis that this would enable the development of DNT cells. We also envisaged that these DNT cells could be activated by bacterial superantigens in vivo as activation of T cells by superantigens does not require CD4 and CD8 coreceptors. Because HLA class II molecules present superantigens more efficiently than murine MHC class II molecules, CD4 CD8 double knockout (DKO) mice transgenically expressing HLA-DR3 or HLA-DQ8 molecules were generated. Although thymic cellularity was comparable between wild type (WT) and DKO mice, CD3+ ab TCR+ thymocytes were significantly reduced in DKO mice, implying defects in thymic-positive selection. Splenic CD3+ ab TCR+ cells and Foxp3+ T regulatory cells were present in DKO mice but significantly reduced. However, the in vivo inflammatory responses and immunopathology elicited by acute challenge with the staphylococcal superantigen enterotoxin B were comparable between WT and DKO mice. Choric exposure to staphylococcal enterotoxin B precipitated a lupus-like inflammatory disease with characteristic lympho-monocytic infiltration in lungs, livers, and kidneys, along with production of anti-nuclear Abs in DKO mice as in WT mice. Overall, our results suggest that DNT cells can develop efficiently in vivo and chronic exposure to bacterial superantigens may precipitate a lupus-like autoimmune disease through activation of DNT cells.

AB - Mature peripheral double negative T (DNT) cells expressing ab TCR but lacking CD4/CD8 coreceptors play protective as well as pathogenic roles. To better understand their development and functioning in vivo, we concomitantly inactivated CD4 and CD8 genes in mice with intact MHC class I and class II molecules with the hypothesis that this would enable the development of DNT cells. We also envisaged that these DNT cells could be activated by bacterial superantigens in vivo as activation of T cells by superantigens does not require CD4 and CD8 coreceptors. Because HLA class II molecules present superantigens more efficiently than murine MHC class II molecules, CD4 CD8 double knockout (DKO) mice transgenically expressing HLA-DR3 or HLA-DQ8 molecules were generated. Although thymic cellularity was comparable between wild type (WT) and DKO mice, CD3+ ab TCR+ thymocytes were significantly reduced in DKO mice, implying defects in thymic-positive selection. Splenic CD3+ ab TCR+ cells and Foxp3+ T regulatory cells were present in DKO mice but significantly reduced. However, the in vivo inflammatory responses and immunopathology elicited by acute challenge with the staphylococcal superantigen enterotoxin B were comparable between WT and DKO mice. Choric exposure to staphylococcal enterotoxin B precipitated a lupus-like inflammatory disease with characteristic lympho-monocytic infiltration in lungs, livers, and kidneys, along with production of anti-nuclear Abs in DKO mice as in WT mice. Overall, our results suggest that DNT cells can develop efficiently in vivo and chronic exposure to bacterial superantigens may precipitate a lupus-like autoimmune disease through activation of DNT cells.

UR - http://www.scopus.com/inward/record.url?scp=85019877034&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019877034&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1601991

DO - 10.4049/jimmunol.1601991

M3 - Article

VL - 198

SP - 4413

EP - 4424

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 11

ER -