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“You Look Familiar…”
How the immune system specifically targets and kills infected cells
Homestead SMART Team: Rahul Subramanian, Sahitya Raja, Nikhil Ramnarayan, Sophia Dantoin, Dhruv Metha, Yelena Ostrerov
Instructor: Ms. Chris Schultz
Mentor: Andrea Ferrante, MD, BRI - BloodCenter of Wisconsin
Abstract
The Acquired Immune
System offers highly specific
protection from infection by
viruses, bacteria and other
microbes by recognizing the
pathogen, triggering an
immune response resulting in
pathogen elimination, and
establishing immunological
memory for future
recognition.
A particular type of response
involves T-lymphocytes,
which play regulatory
and/or killing functions. In
particular, cytotoxic Tlymphocytes (CTL) identify
and kill infected cells by
examining pieces of proteins
(antigens) on the cell
membrane as here
illustrated by the CTL
response to the influenza
virus. Each CTL scans the
antigen repertoire with its
receptor (TCR), and upon
binding with a cognate
complex, destroys the
infected cell.
1. Infection
Structural
Considerations
Host Cell
Viral peptide
pieces
Influenza Virus
In the model pictured below, due to the specific
recognition by the TCR JM22 (left) of the viral
peptide MP 58-66 presented within the Class-I
HLA-A2 protein (right) , the host cell will be killed.
MHC
A cell is infected by an influenza
virus. A viral peptide is transported to
the ER, where it is encased in an
MHC Class-I presentation protein.
2. Presentation
We present the outstanding
model of an influenzaderived peptide (MP (58-66))
bound to HLA-A2 (a
membrane molecule which
presents antigens to T cells),
and complexed with the
TCR Vβ17Vα10.2.
Host Cell
MHC
4. Killing and apoptosis
PDB ID 1OGA.pdb
The MHC- peptide complex is
transported to the cell membrane,
where the MHC presents the
peptide.
Conclusion
The CTL response to the HLA-A2/MP(58–66) complex can be an instructive
model of immune memory to an antigen of a frequently encountered virus
that usually is cleared from the body. Interestingly, this response mainly
recruits T cells bearing particular TCR-α and β chains. TCR Vβ17 accounts
for between 55 and 85% of all β chains used in this response, and we
showed the structural characteristics giving reason to this phenomenon.
Moreover, the observation here presented suggests that this domain may
have coevolved with the HLA-A2 to respond to the strong selection
pressure of recurrent and often lethal influenza pandemics.
Upon recognition of the peptide, the
T cell immediately destroys the host
cell. If the T cell fails to recognize the
cell, it continues to examine other
cells in the area.
T cell
TCR
MHC
Host cell
3. Recognition
A T cell able to recognize a specific
peptide sequence scans the peptide
using its T Cell Receptor.
A SMART Team project supported by the National Institutes of Health (NIH)
– National Center for Research Resources Science Education Partnership
Award (NCRR-SEPA)
Each chain of the TCR possesses
one variable (V) domain, one
constant (C) domain, a transmembrane/cell membranespanning region, and a short
cytoplasmic tail at the C-terminal
end. The final structure is the
outcome of a rearrangement
process at the DNA level during
which one gene segment among
several encoding for each domain
is randomly selected and joined
with the others. In our model, there
are four crucial hotspot residues for
TCR binding. Of these, three are
encoded by a TCR gene sequence
known as V β (β chain) 17 (gene
segment number) which is stable
through T cell development. The
fourth is encoded by a high number
of codons in a gene portion which is
modified during cell development.
It seems plausible that the number
of T cells with Vβ17 receptors which
are capable of binding the HLA-A2flu is higher than other HLA-A2-fluspecific TCRs, and may explain the
dominance of this CTL response.
Depletion of T
cells with Vβ17
receptors from
a cell culture
dramatically
decreases the
ability of the
remaining T
cell population
to kill fluinfected cells
References
P.J. Lehner, E.C. Wang, P.A. Moss, S. Williams, K. Platt, S.M.
Friedman, J.I. Bell and L.K. Borysiewicz, Human HLA-A0201restricted cytotoxic T lymphocyte recognition of influenza A is
dominated by T cells bearing the V beta 17 gene segment, J.
Exp. Med. 181 (1995), pp. 79–91
Stewart - Jones, Guillaume B E, Andrew J. McMichael, John I.
Bell, David I. Stuart, and Yvonne E. Jones. "A Structural Basis
for Immunodominant Human T Cell Receptor Recognition."
Nature Immunology (2003): 1-4.