TY - JOUR
T1 - An evidence for surface expression of an immunogenic epitope of sarcoplasmic/endoplasmic reticulum calcium-ATPase2a on antigen-presenting cells from naive mice in the mediation of autoimmune myocarditis
AU - Arumugam, Rajkumar
AU - Yalaka, Bharathi
AU - Massilamany, Chandirasegaran
AU - Haider Ali, M. S.Shihabudeen
AU - Lasrado, Ninaad
AU - Jayaraja, Sabarirajan
AU - Riethoven, Jean Jack
AU - Sun, Xinghui
AU - Reddy, Jay
N1 - Publisher Copyright:
© 2019 Elsevier GmbH
PY - 2020/3
Y1 - 2020/3
N2 - We recently reported identification of sarcoplasmic/endoplasmic reticulum calcium-ATPase2a (SERCA2a) 971-990, which induces atrial myocarditis by generating autoreactive T cells in A/J mice. However, it was unknown how antigen-sensitized T cells could recognize SERCA2a 971-990, since SERCA2a-expression is confined to an intracellular compartment. In this report, we present evidence that antigen-presenting cells (APCs) from lymphoid and non-lymphoid organs in naïve animals present SERCA2a 971-990 and stimulate antigen-specific T cells. Using major histocompatibility complex (MHC) class II dextramers for SERCA2a 971-990, we created a panel of T cell hybridomas and demonstrated that splenocytes from naïve A/J mice stimulated the hybridoma cells without exogenous supplementation of SERCA2a 971-990. We then recapitulated this phenomenon by using SERCA2a 971-990 -specific primary T cells, verifying that the T cell responses were MHC-restricted. Furthermore, SERCA2a 971-990 -sensitzed T cells exposed to APCs from naïve mice were found to produce the inflammatory cytokines interferon-γ, granulocyte macrophage colony stimulating factor, and interleukin-17A, which are implicated in the induction of myocarditis. Finally, while T cells exposed to mononuclear cells (MNCs) obtained from heart and liver also responded similarly to splenocytes, endothelial cells (ECs) generated from the corresponding organs displayed opposing effects, in that the proliferative responses were suppressed with the heart ECs, but not with the liver ECs. Taken together, our data suggest that the surface expression of SERCA2a 971-990 by naïve APCs can potentially trigger pathogenic autoreactive T cell responses under conditions of autoimmunity, which may have implications in endothelial dysfunction.
AB - We recently reported identification of sarcoplasmic/endoplasmic reticulum calcium-ATPase2a (SERCA2a) 971-990, which induces atrial myocarditis by generating autoreactive T cells in A/J mice. However, it was unknown how antigen-sensitized T cells could recognize SERCA2a 971-990, since SERCA2a-expression is confined to an intracellular compartment. In this report, we present evidence that antigen-presenting cells (APCs) from lymphoid and non-lymphoid organs in naïve animals present SERCA2a 971-990 and stimulate antigen-specific T cells. Using major histocompatibility complex (MHC) class II dextramers for SERCA2a 971-990, we created a panel of T cell hybridomas and demonstrated that splenocytes from naïve A/J mice stimulated the hybridoma cells without exogenous supplementation of SERCA2a 971-990. We then recapitulated this phenomenon by using SERCA2a 971-990 -specific primary T cells, verifying that the T cell responses were MHC-restricted. Furthermore, SERCA2a 971-990 -sensitzed T cells exposed to APCs from naïve mice were found to produce the inflammatory cytokines interferon-γ, granulocyte macrophage colony stimulating factor, and interleukin-17A, which are implicated in the induction of myocarditis. Finally, while T cells exposed to mononuclear cells (MNCs) obtained from heart and liver also responded similarly to splenocytes, endothelial cells (ECs) generated from the corresponding organs displayed opposing effects, in that the proliferative responses were suppressed with the heart ECs, but not with the liver ECs. Taken together, our data suggest that the surface expression of SERCA2a 971-990 by naïve APCs can potentially trigger pathogenic autoreactive T cell responses under conditions of autoimmunity, which may have implications in endothelial dysfunction.
KW - APCs
KW - Autoimmunity
KW - Autoreactive T cells
KW - Mouse model
KW - Myocarditis
KW - Self-antigens
KW - T cells and SERCA2a
UR - http://www.scopus.com/inward/record.url?scp=85076825817&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076825817&partnerID=8YFLogxK
U2 - 10.1016/j.imbio.2019.12.005
DO - 10.1016/j.imbio.2019.12.005
M3 - Article
C2 - 31870642
AN - SCOPUS:85076825817
SN - 0171-2985
VL - 225
JO - Immunobiology
JF - Immunobiology
IS - 2
M1 - 151896
ER -