2 research outputs found
Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition
In cellular immunity,
T cells recognize peptide antigens bound
and presented by major histocompatibility complex (MHC) proteins.
The motions of peptides bound to MHC proteins play a significant role
in determining immunogenicity. However, existing approaches for investigating
peptide/MHC motional dynamics are challenging or of low throughput,
hindering the development of algorithms for predicting immunogenicity
from large databases, such as those of tumor or genetically unstable
viral genomes. We addressed this by performing extensive molecular
dynamics simulations on a large structural database of peptides bound
to the most commonly expressed human class-I MHC protein, HLA-A*0201.
The simulations reproduced experimental indicators of motion and were
used to generate simple models for predicting site-specific, rapid
motions of bound peptides through differences in their sequence and
chemical composition alone. The models can easily be applied on their
own or incorporated into immunogenicity prediction algorithms. Beyond
their predictive power, the models provide insight into how amino
acid substitutions can influence peptide and protein motions and how
dynamic information is communicated across peptides. They also indicate
a link between peptide rigidity and hydrophobicity, two features known
to be important in influencing cellular immune responses
DataSheet_1_Geometric parameters that affect the behavior of logic-gated CAR T cells.pdf
Clinical applications of CAR-T cells are limited by the scarcity of tumor-specific targets and are often afflicted with the same on-target/off-tumor toxicities that plague other cancer treatments. A new promising strategy to enforce tumor selectivity is the use of logic-gated, two-receptor systems. One well-described application is termed Tmodâ„¢, which originally utilized a blocking inhibitory receptor directed towards HLA-I target antigens to create a protective NOT gate. Here we show that the function of Tmod blockers targeting non-HLA-I antigens is dependent on the height of the blocker antigen and is generally compatible with small, membrane-proximal targets. We compensate for this apparent limitation by incorporating modular hinge units to artificially extend or retract the ligand-binding domains relative to the effector cell surface, thereby modulating Tmod activator and blocker function. By accounting for structural differences between activator and blocker targets, we developed a set of simple geometric parameters for Tmod receptor design that enables targeting of blocker antigens beyond HLA-I, thereby broadening the applications of logic-gated cell therapies.</p