Frustration and cooperativity during selection of the T cell repertoireApril 23rd, 2008MIT Building 24, Room 121Arup Chakraborty
MIT
The orchestrators of adaptive immunity are a class of cells called T lymphocytes
(T cells). They express T cell receptor (TCR) molecules on their surface, which
recognize molecular signatures of pathogens. Each T cell expresses a distinct
TCR, which can bind to short peptides (p) associated with products of the major
histocompatibility (MHC) genes. Sufficiently strong binding of TCR to
pathogen-derived pMHC molecules results in T cell activation. TCR can recognize
pathogenic pMHC quite specifically, yet a particular TCR can recognize many
pathogen-derived pMHC. The diverse repertoire of TCR also enables recognition
of diverse pathogens. TCR binding to endogenous (or ?self?) pMHC molecules
does not result in frequent autoimmune responses. This specific (yet,
cross-reactive), diverse, and self-tolerant T cell repertoire is designed in
the thymus. I will detail how an approach that brings together theoretical and
computational studies (rooted in statistical physics) with experiments (carried
out by key collaborators) has allowed us to shed light on the mechanistic
principles underlying the design of the T cell repertoire in the thymus. I
will first present some molecular studies of cooperative signaling events that
lead to positive and negative selection. I will then highlight how frustration
plays a key role in designing pathogen-specific, yet diverse, T cells. I will
also show how short peptides (~ 10 amino acids) are sufficient for sampling the
endogenous proteome, while still allowing discrimination of ?self? and
?foreign? pMHC.