Differential Signaling and Hierarchical
Response Thresholds Induced by an
Immunodominant Peptide of Myelin Basic
Protein and an Altered Peptide Ligand in
Human T Cells
Paul D. Crowe, Stefen A. Boehme, Tim Wong,
Amitabh Gaur, John Sidney, Alessandro Sette, and
Paul J. Conlon
ABSTRACT: Changes in peptide antigen concentration
or structure can have a profound effect on T cell respon-
siveness by inducing selected T cell effector functions. In
this study, we have compared the biological responses of
an MBP83-99-specific human T
h
0 T cell clone (TCC)
stimulated with increasing concentrations of native pep-
tide or an altered peptide ligand (APL). Our results show
that the hierarchy of response thresholds for proliferation
and cytokine secretion is similar for native peptide and
APL. However, because a much higher concentration of
the APL is required to evoke the same degree of response,
the cytokine profile is shifted towards a T
h
2-like response
relative to the same concentration of native peptide. In
addition, we observed qualitative differences in TCR sig-
nal transduction triggered by native peptide and a weak
agonist APL even at concentrations that elicit similar
biological responses. Thus, the relationship between TCR
signaling and biological responses may be more complex
than previously recognized. Human Immunology 59,
679 – 689 (1998). © American Society for Histocompat-
ibility and Immunogenetics, 1998. Published by Elsevier
Science Inc.
ABBREVIATIONS
MBP myelin basic protein
APL altered peptide ligand
EBV Epstein-Barr virus
TCC T cell clone
INTRODUCTION
Recognition of MHC-peptide ligand complexes by T cell
antigen receptors initiates a wide range of effector func-
tions including clonal expansion and production of cy-
tokines which determine the nature and magnitude of
the ensuing immune response [1]. Functionally distinct
subsets of murine T
h
cells have been described based
upon the cytokines they secrete [2]. T
h
1 cells are char-
acterized by their ability to produce IFN- and TNF
that enhance cellular immunity, whereas T
h
2 cells se-
crete IL-4, IL-5 and IL-10, promoting humoral immu-
nity. For human T lymphocytes, the demarcation be-
tween functional T
h
subtypes is not as well defined and
some cells, designated T
h
0, are characterized by their
ability to produce both T
h
1 and T
h
2 cytokines. The
functional subtype of a given T lymphocyte has impor-
tant implications both in terms of immune responsive-
ness to pathogens and autoimmunity. In the case of
autoimmunity, previous work has shown that T
h
1 cells
play a major role in the pathogenesis of multiple sclerosis
(MS) and experimental autoimmune encephalomyelitis
(EAE), the murine model of the disease. Other studies
have implicated T
h
2 cytokines in the natural recovery
from disease [3–5]. Thus, the balance of cytokines se-
From Neurocrine Biosciences, Inc., 10555 Science Center Drive (P.D.C.,
S.A.B., T.W., A.G., P.J.C.) and Epimmune, Inc., 6555 Nancy Ridge
Drive (J.S., A.S.), San Diego, CA 92121, USA.
Address reprint requests to: Dr. Paul D. Crowe, Neurocrine Biosciences,
Inc., 10555 Science Center Drive, San Diego, CA 92121, USA; Tel: (619)
658-7669; Fax: (619) 658-7601; E-Mail: pcrowe@neurocrine.com.
Received July 6, 1998; accepted July 28, 1998.
Human Immunology 59, 679 – 689 (1998)
0198-8859/98/$19.00 © American Society for Histocompatibility and Immunogenetics, 1998
Published by Elsevier Science Inc. PII S0198-8859(98)00077-9