Cambridge University                               TCM seminar                           9 November 2023

Diversity, tolerance, and maturation of the adaptive immune response

Outline

I.       The adaptive immune system: B cells, T cells- diverse, self-tolerant, and specific                                       

II.      Thymic Selection: positive and negative selection, specificity from weak amino-acids, extreme value distribution

III.     Quorum sensing for peripheral tolerance

IV.     B cells: Viruses, Antibodies, Antigens, and the puzzle of low HIV spike density                                    

V.      Affinity Maturation: Germinal Center, Rapid evolution of antibodies, Fisher and Price equations

VI.      Fitness & Evolution: Competition for virus capture and proliferation signal from helper T cells

VII.     Optimal density for eliciting potent antibodies; implications for nanoparticle vaccination & HIV spikes

VIII.   Broadly neutralizing Antibodies: Controlling affinity maturation against a mutable virus

IX.     Summary

Next (Adaptive immunity) Outline B cells Affinity Maturation Fitness & Evolution Optimal density Broadly neutralizing Abs Multiple Ag Summary

The adaptive immune system protects the body from the ever-changing landscape of foreign microorganisms. The two arms of the adaptive immune system, T cells and B cells, mount specific responses to pathogens by utilizing the diversity of their receptors, generated through hypermutation.  B cells generate antibodies that strongly bind and inactivate antigens (toxic targets). Potent antibodies are generated through the process of “Affinity Maturation" which is akin to evolution at a rapid pace. T cells recognize and clear infected hosts when their highly variable receptors bind sufficiently strongly to complexes formed with antigen-derived peptides displayed on the cell surface. To avoid auto-immune responses, a process of "Thymic Selection" ensures that only self-tolerant receptors (binding weakly to self peptides) are engaged. Methods from Statistical Physics can be used to model and elucidate these processes, as will be demonstrated through several examples.