Developmental Biology - Immune Response Activity|
How Immune Cells Choose to Respond
Viruses and other disease-causing microbes influence the type of immune response a host will develop...
In some cases, the predominant response involves antibodies — proteins made by the immune system that specifically recognize invading microbe parts 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 mechanisms leading to either antibody or cell-mediated response.
About 10 years ago, a novel signal was suggested as the trigger for a cell-mediated response.
In the current study, Baylor researchers: William Decker, Matthew Halpert, Vanaja Konduri and colleagues present comprehensive evidence that supports this phenomenon and proposes a mechanism for its action.
The Classic Immune Response
Research has shown there are two factors related to microbes that will significantly affect the predominate immune response.
Microbial components (parts of proteins or genetic material, called pathogen-associated molecular patterns or PAMPs tend to be inside or outside cells.
• When viral genetic material is detected inside cells, a cell-mediated immune response develops.
• When detection of viral proteins is outside the cell, an antibody-mediated response is triggered.
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, alerting the immune system to the presence of a foreign microbial invader.
Novel Mechanism Triggers Cell-mediated Immune Response
In addition to these well-studied signals that mediate classic immune responses, Baylor researchers proposed and demonstrated a different mechanism that directs the immune response toward a cellular type. This new mechanism involves surveillance of both the intracellular and extracellular environments by a different class of proteins called the Major Histocompatibility Complex, or MHC.
MHC Class I binds protein fragments found inside cells whereas MHC Class II binds protein fragments present outside the cells.
"This mechanism appears to take place mostly when a fulminant viral infection occurs."
William K. Decker PhD, Associate Professor, Pathology and Immunology, member of the Dan L Duncan Comprehensive Cancer Center, and corresponding author of this work.
When a virus avidly proliferates, parts of viral proteins can be found in abundance both inside and outside cell walls. In this situation, one possible outcome is that identical protein fragments bind to both MHC Class I and Class II proteins on antigen-presenting cells.
According to Decker, when this occurs in conjunction with other inflammatory cues, "a response is triggered that promotes a cell-mediated immunity against that virus. 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 identical amino acid sequences."
"In this study, we defined experimental model systems which enabled us to study this specific mechanism without interference from classical mechanisms. We found ample evidence to support the novel mechanism and described a large molecular sensor complex we propose plays a central role in comparing amino acids sequences of intracellular and extracellular protein fragments," explains Matthew M. Halpert PhD, 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 lasting longer than antibody-mediated immunity induced by certain vaccines.
The authors propose this novel mechanism steering 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 basic research study is published in the journal of the Federation of American Societies for Experimental Biology (FASEB).
Mammalian immune responses are initiated by “danger” signals — immutable molecular structures known as PAMPs. When detected by fixed, germline encoded receptors, pathogen-associated molecular pattern (PAMPs) subsequently inform the polarization of downstream adaptive responses depending upon identity and localization of the PAMP. Here, we report the existence of a completely novel “PAMP” that is not a molecular structure but an antigenic pattern. This pattern––the incidence of peptide epitopes with stretches of 100% sequence identity bound to both dendritic cell (DC) major histocompatibility (MHC) class I and MHC class II––strongly induces TH1 immune polarization and activation of the cellular immune response. Inherent in the existence of this PAMP is the concomitant existence of a molecular sensor complex with the ability to scan and compare amino acid sequence identities of bound class I and II peptides. We provide substantial evidence implicating the multienzyme aminoacyl-tRNA synthetase (mARS) complex and its AIMp1 structural component as the key constituents of this complex. The results demonstrate a wholly novel mechanism by which T-helper (TH) polarization is governed and provide critical information for the design of vaccination strategies intended to provoke cell-mediated immunity.
Matthew M. Halpert Vanaja Konduri, Dan Liang, Jonathan Vazquez-Perez, Colby J. Hofferek, Scott A. Weldon, Yunyu Baig, Indira Vedula, Jonathan M. Levitt and William K. Decker.
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).
HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID). Grant Number: AI127387 Cancer Prevention and Research Institute of Texas (CPRIT). Grant Number: RP110545.
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Artist's model of a dendritic cell, based on three-dimensional focused ion beam
scanning electron microscopy (FIB-SEM) data. CREDIT National Cancer Institute