Murine T cell maturation entails protection from Mbl2, but complement proteins do not drive clearance of cells that fail maturation in the absence of NKAP

Barsha Dash, Paul J. Belmonte, Sydney R. Fine, Michael J. Shapiro, Ji Young Chung, Aaron D. Schwab, Shaylene A. McCue, Matthew J. Rajcula, Virginia M Shapiro

Research output: Contribution to journalArticle

Abstract

Recent thymic emigrants that fail postpositive selection maturation are targeted by complement proteins. T cells likely acquire complement resistance during maturation in the thymus, a complement-privileged organ. To test this, thymocytes and fresh serum were separately obtained and incubated together in vitro to assess complement deposition. Complement binding decreased with development and maturation. Complement binding decreased from the double-positive thymocyte to the single-positive stage, and within single-positive thymocytes, complement binding gradually decreased with increasing intrathymic maturation. Binding of the central complement protein C3 to wild-type immature thymocytes required the lectin but not the classical pathway. Specifically, MBL2 but not MBL1 was required, demonstrating a unique function for MBL2. Previous studies demonstrated that the loss of NKAP, a transcriptional regulator of T cell maturation, caused peripheral T cell lymphopenia and enhanced complement susceptibility. To determine whether complement causes NKAP-deficient T cell disappearance, both the lectin and classical pathways were genetically ablated. This blocked C3 deposition on NKAP-deficient T cells but failed to restore normal cellularity, indicating that complement contributes to clearance but is not the primary cause of peripheral T cell lymphopenia. Rather, the accumulation of lipid peroxides in NKAP-deficient T cells was observed. Lipid peroxidation is a salient feature of ferroptosis, an iron-dependent nonapoptotic cell death. Thus, wild-type thymocytes naturally acquire the ability to protect themselves from complement targeting by MBL2 with maturation. However, NKAP-deficient immature peripheral T cells remain scarce in complement-deficient mice likely due to ferroptosis.

Original languageEnglish (US)
Pages (from-to)408-417
Number of pages10
JournalJournal of Immunology
Volume203
Issue number2
DOIs
StatePublished - Jan 1 2019

Fingerprint

Complement System Proteins
T-Lymphocytes
Thymocytes
Lymphopenia
Lectins
Complement C3
Lipid Peroxides
Thymus Gland
Lipid Peroxidation
Cell Death
Iron
Serum

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Murine T cell maturation entails protection from Mbl2, but complement proteins do not drive clearance of cells that fail maturation in the absence of NKAP. / Dash, Barsha; Belmonte, Paul J.; Fine, Sydney R.; Shapiro, Michael J.; Chung, Ji Young; Schwab, Aaron D.; McCue, Shaylene A.; Rajcula, Matthew J.; Shapiro, Virginia M.

In: Journal of Immunology, Vol. 203, No. 2, 01.01.2019, p. 408-417.

Research output: Contribution to journalArticle

Dash, Barsha ; Belmonte, Paul J. ; Fine, Sydney R. ; Shapiro, Michael J. ; Chung, Ji Young ; Schwab, Aaron D. ; McCue, Shaylene A. ; Rajcula, Matthew J. ; Shapiro, Virginia M. / Murine T cell maturation entails protection from Mbl2, but complement proteins do not drive clearance of cells that fail maturation in the absence of NKAP. In: Journal of Immunology. 2019 ; Vol. 203, No. 2. pp. 408-417.
@article{a9e9fa151b4446159dccba999fa030df,
title = "Murine T cell maturation entails protection from Mbl2, but complement proteins do not drive clearance of cells that fail maturation in the absence of NKAP",
abstract = "Recent thymic emigrants that fail postpositive selection maturation are targeted by complement proteins. T cells likely acquire complement resistance during maturation in the thymus, a complement-privileged organ. To test this, thymocytes and fresh serum were separately obtained and incubated together in vitro to assess complement deposition. Complement binding decreased with development and maturation. Complement binding decreased from the double-positive thymocyte to the single-positive stage, and within single-positive thymocytes, complement binding gradually decreased with increasing intrathymic maturation. Binding of the central complement protein C3 to wild-type immature thymocytes required the lectin but not the classical pathway. Specifically, MBL2 but not MBL1 was required, demonstrating a unique function for MBL2. Previous studies demonstrated that the loss of NKAP, a transcriptional regulator of T cell maturation, caused peripheral T cell lymphopenia and enhanced complement susceptibility. To determine whether complement causes NKAP-deficient T cell disappearance, both the lectin and classical pathways were genetically ablated. This blocked C3 deposition on NKAP-deficient T cells but failed to restore normal cellularity, indicating that complement contributes to clearance but is not the primary cause of peripheral T cell lymphopenia. Rather, the accumulation of lipid peroxides in NKAP-deficient T cells was observed. Lipid peroxidation is a salient feature of ferroptosis, an iron-dependent nonapoptotic cell death. Thus, wild-type thymocytes naturally acquire the ability to protect themselves from complement targeting by MBL2 with maturation. However, NKAP-deficient immature peripheral T cells remain scarce in complement-deficient mice likely due to ferroptosis.",
author = "Barsha Dash and Belmonte, {Paul J.} and Fine, {Sydney R.} and Shapiro, {Michael J.} and Chung, {Ji Young} and Schwab, {Aaron D.} and McCue, {Shaylene A.} and Rajcula, {Matthew J.} and Shapiro, {Virginia M}",
year = "2019",
month = "1",
day = "1",
doi = "10.4049/jimmunol.1801443",
language = "English (US)",
volume = "203",
pages = "408--417",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "2",

}

TY - JOUR

T1 - Murine T cell maturation entails protection from Mbl2, but complement proteins do not drive clearance of cells that fail maturation in the absence of NKAP

AU - Dash, Barsha

AU - Belmonte, Paul J.

AU - Fine, Sydney R.

AU - Shapiro, Michael J.

AU - Chung, Ji Young

AU - Schwab, Aaron D.

AU - McCue, Shaylene A.

AU - Rajcula, Matthew J.

AU - Shapiro, Virginia M

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Recent thymic emigrants that fail postpositive selection maturation are targeted by complement proteins. T cells likely acquire complement resistance during maturation in the thymus, a complement-privileged organ. To test this, thymocytes and fresh serum were separately obtained and incubated together in vitro to assess complement deposition. Complement binding decreased with development and maturation. Complement binding decreased from the double-positive thymocyte to the single-positive stage, and within single-positive thymocytes, complement binding gradually decreased with increasing intrathymic maturation. Binding of the central complement protein C3 to wild-type immature thymocytes required the lectin but not the classical pathway. Specifically, MBL2 but not MBL1 was required, demonstrating a unique function for MBL2. Previous studies demonstrated that the loss of NKAP, a transcriptional regulator of T cell maturation, caused peripheral T cell lymphopenia and enhanced complement susceptibility. To determine whether complement causes NKAP-deficient T cell disappearance, both the lectin and classical pathways were genetically ablated. This blocked C3 deposition on NKAP-deficient T cells but failed to restore normal cellularity, indicating that complement contributes to clearance but is not the primary cause of peripheral T cell lymphopenia. Rather, the accumulation of lipid peroxides in NKAP-deficient T cells was observed. Lipid peroxidation is a salient feature of ferroptosis, an iron-dependent nonapoptotic cell death. Thus, wild-type thymocytes naturally acquire the ability to protect themselves from complement targeting by MBL2 with maturation. However, NKAP-deficient immature peripheral T cells remain scarce in complement-deficient mice likely due to ferroptosis.

AB - Recent thymic emigrants that fail postpositive selection maturation are targeted by complement proteins. T cells likely acquire complement resistance during maturation in the thymus, a complement-privileged organ. To test this, thymocytes and fresh serum were separately obtained and incubated together in vitro to assess complement deposition. Complement binding decreased with development and maturation. Complement binding decreased from the double-positive thymocyte to the single-positive stage, and within single-positive thymocytes, complement binding gradually decreased with increasing intrathymic maturation. Binding of the central complement protein C3 to wild-type immature thymocytes required the lectin but not the classical pathway. Specifically, MBL2 but not MBL1 was required, demonstrating a unique function for MBL2. Previous studies demonstrated that the loss of NKAP, a transcriptional regulator of T cell maturation, caused peripheral T cell lymphopenia and enhanced complement susceptibility. To determine whether complement causes NKAP-deficient T cell disappearance, both the lectin and classical pathways were genetically ablated. This blocked C3 deposition on NKAP-deficient T cells but failed to restore normal cellularity, indicating that complement contributes to clearance but is not the primary cause of peripheral T cell lymphopenia. Rather, the accumulation of lipid peroxides in NKAP-deficient T cells was observed. Lipid peroxidation is a salient feature of ferroptosis, an iron-dependent nonapoptotic cell death. Thus, wild-type thymocytes naturally acquire the ability to protect themselves from complement targeting by MBL2 with maturation. However, NKAP-deficient immature peripheral T cells remain scarce in complement-deficient mice likely due to ferroptosis.

UR - http://www.scopus.com/inward/record.url?scp=85068939368&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068939368&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1801443

DO - 10.4049/jimmunol.1801443

M3 - Article

C2 - 31175160

AN - SCOPUS:85068939368

VL - 203

SP - 408

EP - 417

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 2

ER -