Novel mechanism triggers a cellular immune response

Date:
June 12, 2020
Source:
Baylor College of Medicine
Summary:
Researchers present comprehensive evidence that supports a novel
trigger for a cell-mediated response and propose a mechanism for
its action.



FULL STORY ========================================================================== Viruses and other disease-causing microbes influence the type of immune response their hosts will develop against them. In some cases, the
predominant response involves antibodies, proteins made by the immune
system that specifically recognize parts of the invading microbe and
mediate its destruction. In other cases, immune cells are trained to
recognize the microbe and lead the attack against it.


========================================================================== Scientists have extensively investigated the mechanisms that lead to
either an antibody or a cell-mediated response, and about 10 years
ago, a novel signal was suggested as the trigger of a cell-mediated
response. In a current study, Baylor researchers, Dr. William Decker,
Dr. Matthew Halpert, Dr. Vanaja Konduri and their colleagues present comprehensive evidence that supports this phenomenon and propose a
mechanism for its action.

The classic immune response Research has shown that two factors related
to microbes significantly affect the type of immune response that
will predominate. On one hand are the microbial components (parts of
proteins or genetic material, called pathogen- associated molecular
patterns or PAMPs), and on the other is the location of the microbes,
whether they tend to be inside or outside cells. Cells have means to
recognize PAMPs ? some cellular proteins recognize PAMPs inside cells,
while others detect PAMPs outside cells.

Research on viruses has shown that when viral genetic material is
detected inside cells, a cell-mediated immune response develops, while the detection of viral proteins outside the cell triggers antibody-mediated responses.

The implementation of these immune responses involves cellular proteins
called Pattern Recognition Receptors, or PRRs. Antigen-presenting cells,
such as dendritic cells, are involved in the first steps of developing a specific immune response. During these first steps, antigen-presenting
cells sample both the intracellular and extracellular environments by
binding PAMPs to their PRRs. Recognition of a PAMP by a PRR turns on the
danger alarm and alerts the rest of the immune system to the presence
of a foreign microbial invader.



==========================================================================
A novel mechanism that triggers a cell-mediated immune response In
addition to these well-studied signals that mediate classic immune
responses, Baylor researchers have proposed and demonstrated a different mechanism that directs the immune response toward a cellular type. This
new mechanism also involves surveillance of both the intracellular and extracellular environments but by a different class of proteins called
the Major Histocompatibility Complex, or MHC. MHC Class I binds protein fragments found inside of cells whereas MHC Class II binds protein
fragments present on the outside of cells.

"This mechanism appears to take place mostly when a fulminant viral
infection occurs," said Decker, associate professor of pathology and
immunology and corresponding author of this work.

When a virus avidly proliferates, parts of viral proteins can be found in abundance both inside and outside of cells. One possible outcome of this situation is that identical protein fragments bind to both MHC Class I
and Class II proteins on antigen-presenting cells.

When this occurs in conjunction with other inflammatory cues, "a
response is triggered that promotes a cell-mediated immunity against
that virus," said Decker, who also is a member of Baylor's Dan L Duncan Comprehensive Cancer Center. "In this case, the response does not depend
on any particular PAMP structure. Instead, it depends on the fact that
the pieces of virus bound by MHC Class I and II have an identical amino
acid sequence." "In this study, we defined experimental model systems
that enabled us to study this specific mechanism without interference
from classical mechanisms. We found ample evidence that supports the
novel mechanism and described a large molecular sensor complex we
propose plays a central role in comparing the amino acids sequences
of intracellular and extracellular protein fragments," said Halpert,
instructor of immunology at Baylor and first author of this work.

"Although further research is needed, we anticipate that this novel
mechanism has potential important clinical applications." Research has
shown that naturally developed cell-mediated immunity against viral
infections tends to confer protection that lasts longer than antibody-
mediate immunity, which is induced by some vaccines. The authors propose
that this novel mechanism that steers the immune response toward the
cellular type offers a valuable opportunity to design vaccines that may
induce more effective and durable cell-based immunity against current
and future viral diseases as well as against cancers. Importantly,
the Decker group is implementing this strategy in clinical trials,
including a study for intent to treat pancreatic cancer (NCT04157127)
due to open in June 2020 at Baylor St. Luke's Medical Center.

This study was supported in part by the Cancer Prevention and Research Institute of Texas (CPRIT) grant RP110545, a Reach Award from Alex's
Lemonade Stand Childhood Cancer Foundation and NIH R01 AI127387. This
project was also supported in part by the Cytometry and Cell Sorting
Core at Baylor College of Medicine with funding from the NIH (AI036211, CA125123, and RR024574).


========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Original written by Ana Mari'a Rodri'guez, Ph.D.. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Matthew M. Halpert, Vanaja Konduri, Dan Liang, Jonathan
Vazquez‐Perez, Colby J. Hofferek, Scott A. Weldon, Yunyu Baig,
Indira Vedula, Jonathan M. Levitt, William K. Decker. MHC class I
and II peptide homology regulates the cellular immune response. The
FASEB Journal, 2020; 34 (6): 8082 DOI: 10.1096/fj.201903002R ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200612120148.htm

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