CD8+ T cells are necessary for recognition of allelic, but not locus-mismatched or xeno-, HLA class I transplantation antigens

Steven H. Borenstein, J. Graham, X. L. Zhang, J. W. Chamberlain

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Although HLA transgenic mice (HLA TgM) could provide a powerful approach to investigate human MHC-specific T cell responsiveness, the extent to which these molecules are recognized by the mouse immune system remains unclear. We established TgM expressing HLA class I alleles A2, B7, or B27 in their fully native form (HLA(nat)) or as hybrid molecules (HLA(hyb)) of the HLA αl/α2 domains linked to the H-2Kb α3, transmembrane, and cytoplasmic domains (i.e., to maintain possible species-specific interactions). Comparison of each as xeno- (i.e., by non-TgM) vs allo- (i.e., by TgM carrying an alternate HLA allele) transplantation Ags revealed the following: 1) Although HLA(hyb) molecules induced stronger xeno-CD8+ T cell responses in vitro, additional effector mechanisms must be active in vivo because HLA(nat) skin grafts were rejected faster by non-TgM; 2) gene knockout recipients showed that xenorejection of HLA(nat) and, unexpectedly, HLA(hyb) grafts doesn't depend on CD8+ or CD4+ T cells or B cells; 3) each HLA(hyb) strain developed tolerance to 'self' but rejected allele- (-B27 vs -B7) and locus- (-B vs -A) mismatched grafts, the former requiring CD8+ T cells, the latter by CD8+ T cell-independent mechanisms. The finding that recognition of xeno-HLA(hyb) does not require CD8+ T cells while recognition of the identical molecule in a strictly allo context does, demonstrates an αl/α2 domain-dependent difference in effector mechanism(s). Furthermore, the CD8+ T cell-independence of locus-mis-matched rejection suggests the degree of similarity between self and non-self αl/α2 determines the effector mechanism(s) activated. The HLA Tg model provides a unique approach to characterize these mechanisms and develop tolerance protocols in the context of human transplantation Ags.

Original languageEnglish (US)
Pages (from-to)2341-2353
Number of pages13
JournalJournal of Immunology
Volume165
Issue number5
StatePublished - Sep 1 2000
Externally publishedYes

Fingerprint

Histocompatibility Antigens Class I
Histocompatibility Antigens
HLA Antigens
T-Lymphocytes
Alleles
Transplants
Transplantation
Gene Knockout Techniques
varespladib methyl
Transgenic Mice
Immune System
B-Lymphocytes
Skin

ASJC Scopus subject areas

  • Immunology

Cite this

CD8+ T cells are necessary for recognition of allelic, but not locus-mismatched or xeno-, HLA class I transplantation antigens. / Borenstein, Steven H.; Graham, J.; Zhang, X. L.; Chamberlain, J. W.

In: Journal of Immunology, Vol. 165, No. 5, 01.09.2000, p. 2341-2353.

Research output: Contribution to journalArticle

@article{4264e32ec6cc42a6951266d96db07efc,
title = "CD8+ T cells are necessary for recognition of allelic, but not locus-mismatched or xeno-, HLA class I transplantation antigens",
abstract = "Although HLA transgenic mice (HLA TgM) could provide a powerful approach to investigate human MHC-specific T cell responsiveness, the extent to which these molecules are recognized by the mouse immune system remains unclear. We established TgM expressing HLA class I alleles A2, B7, or B27 in their fully native form (HLA(nat)) or as hybrid molecules (HLA(hyb)) of the HLA αl/α2 domains linked to the H-2Kb α3, transmembrane, and cytoplasmic domains (i.e., to maintain possible species-specific interactions). Comparison of each as xeno- (i.e., by non-TgM) vs allo- (i.e., by TgM carrying an alternate HLA allele) transplantation Ags revealed the following: 1) Although HLA(hyb) molecules induced stronger xeno-CD8+ T cell responses in vitro, additional effector mechanisms must be active in vivo because HLA(nat) skin grafts were rejected faster by non-TgM; 2) gene knockout recipients showed that xenorejection of HLA(nat) and, unexpectedly, HLA(hyb) grafts doesn't depend on CD8+ or CD4+ T cells or B cells; 3) each HLA(hyb) strain developed tolerance to 'self' but rejected allele- (-B27 vs -B7) and locus- (-B vs -A) mismatched grafts, the former requiring CD8+ T cells, the latter by CD8+ T cell-independent mechanisms. The finding that recognition of xeno-HLA(hyb) does not require CD8+ T cells while recognition of the identical molecule in a strictly allo context does, demonstrates an αl/α2 domain-dependent difference in effector mechanism(s). Furthermore, the CD8+ T cell-independence of locus-mis-matched rejection suggests the degree of similarity between self and non-self αl/α2 determines the effector mechanism(s) activated. The HLA Tg model provides a unique approach to characterize these mechanisms and develop tolerance protocols in the context of human transplantation Ags.",
author = "Borenstein, {Steven H.} and J. Graham and Zhang, {X. L.} and Chamberlain, {J. W.}",
year = "2000",
month = "9",
day = "1",
language = "English (US)",
volume = "165",
pages = "2341--2353",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "5",

}

TY - JOUR

T1 - CD8+ T cells are necessary for recognition of allelic, but not locus-mismatched or xeno-, HLA class I transplantation antigens

AU - Borenstein, Steven H.

AU - Graham, J.

AU - Zhang, X. L.

AU - Chamberlain, J. W.

PY - 2000/9/1

Y1 - 2000/9/1

N2 - Although HLA transgenic mice (HLA TgM) could provide a powerful approach to investigate human MHC-specific T cell responsiveness, the extent to which these molecules are recognized by the mouse immune system remains unclear. We established TgM expressing HLA class I alleles A2, B7, or B27 in their fully native form (HLA(nat)) or as hybrid molecules (HLA(hyb)) of the HLA αl/α2 domains linked to the H-2Kb α3, transmembrane, and cytoplasmic domains (i.e., to maintain possible species-specific interactions). Comparison of each as xeno- (i.e., by non-TgM) vs allo- (i.e., by TgM carrying an alternate HLA allele) transplantation Ags revealed the following: 1) Although HLA(hyb) molecules induced stronger xeno-CD8+ T cell responses in vitro, additional effector mechanisms must be active in vivo because HLA(nat) skin grafts were rejected faster by non-TgM; 2) gene knockout recipients showed that xenorejection of HLA(nat) and, unexpectedly, HLA(hyb) grafts doesn't depend on CD8+ or CD4+ T cells or B cells; 3) each HLA(hyb) strain developed tolerance to 'self' but rejected allele- (-B27 vs -B7) and locus- (-B vs -A) mismatched grafts, the former requiring CD8+ T cells, the latter by CD8+ T cell-independent mechanisms. The finding that recognition of xeno-HLA(hyb) does not require CD8+ T cells while recognition of the identical molecule in a strictly allo context does, demonstrates an αl/α2 domain-dependent difference in effector mechanism(s). Furthermore, the CD8+ T cell-independence of locus-mis-matched rejection suggests the degree of similarity between self and non-self αl/α2 determines the effector mechanism(s) activated. The HLA Tg model provides a unique approach to characterize these mechanisms and develop tolerance protocols in the context of human transplantation Ags.

AB - Although HLA transgenic mice (HLA TgM) could provide a powerful approach to investigate human MHC-specific T cell responsiveness, the extent to which these molecules are recognized by the mouse immune system remains unclear. We established TgM expressing HLA class I alleles A2, B7, or B27 in their fully native form (HLA(nat)) or as hybrid molecules (HLA(hyb)) of the HLA αl/α2 domains linked to the H-2Kb α3, transmembrane, and cytoplasmic domains (i.e., to maintain possible species-specific interactions). Comparison of each as xeno- (i.e., by non-TgM) vs allo- (i.e., by TgM carrying an alternate HLA allele) transplantation Ags revealed the following: 1) Although HLA(hyb) molecules induced stronger xeno-CD8+ T cell responses in vitro, additional effector mechanisms must be active in vivo because HLA(nat) skin grafts were rejected faster by non-TgM; 2) gene knockout recipients showed that xenorejection of HLA(nat) and, unexpectedly, HLA(hyb) grafts doesn't depend on CD8+ or CD4+ T cells or B cells; 3) each HLA(hyb) strain developed tolerance to 'self' but rejected allele- (-B27 vs -B7) and locus- (-B vs -A) mismatched grafts, the former requiring CD8+ T cells, the latter by CD8+ T cell-independent mechanisms. The finding that recognition of xeno-HLA(hyb) does not require CD8+ T cells while recognition of the identical molecule in a strictly allo context does, demonstrates an αl/α2 domain-dependent difference in effector mechanism(s). Furthermore, the CD8+ T cell-independence of locus-mis-matched rejection suggests the degree of similarity between self and non-self αl/α2 determines the effector mechanism(s) activated. The HLA Tg model provides a unique approach to characterize these mechanisms and develop tolerance protocols in the context of human transplantation Ags.

UR - http://www.scopus.com/inward/record.url?scp=0034284431&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034284431&partnerID=8YFLogxK

M3 - Article

C2 - 10946256

AN - SCOPUS:0034284431

VL - 165

SP - 2341

EP - 2353

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 5

ER -