Title: Virus Killers and Killer T cells
A major challenge for those of us who are interested in minimizing the toll of infectiousdisease is that RNA viruses with poor genomic fidelity throw off large numbers ofvariants that emerge as viable escape mutants following immune selection. This is a
particular problem for designing vaccines to combat the “killer” viruses that cause AIDS,
hepatitis C and influenza, all of which are major causes of human morbidity andmortality. Of these, our greatest success has been with influenza, though it is necessaryto maintain constant global surveillance and to design new vaccines annually.Considerable effort is being made via the multi-centre HIV/AIDS neutralizing antibodyconsortium to develop strategies for skewing B cell immunity towards more conserved,shared determinants, such as the binding site on the external HIV Env molecule thatengages with the CD4 cell-surface receptor. If successful, there will be a big push toapply such approaches to other pathogens. In the meantime, it is the case that the
“killer” cytotoxic T lymphocytes (CTLs) that are specific for virus peptides presented by
self major histocompatibility complex class I (MHCI) glycoproteins tend to be directed atrelatively conserved virus components. The nature of the effector and memory phasesof CTL-mediated immunity will be discussed, together with the limitations and potentialbenefits of vaccines that emphasize this aspect of host responsiveness.
Role in disease pathogenesis
During hepatitis B virus (HBV) infection cytotoxic T cells play an importantpathogenetic role. They contribute to nearly all of the liver injury associated withHBV infection and, by killing infected cells and by producing antiviral cytokinescapable of purging HBV from viable hepatocytes, cytotoxic T cells also eliminatethe virus.
Recently platelets have been shown to facilitate the accumulation of
virus-specific cytotoxic T cells into the infected liver.
Recently CTLs have beenimplicated in the progression of arthritis:depletion of knee
joint cartilage macromolecules such as glycosaminoglycans by CTLs
and macrophages has been observed in a rat model of the disease.
Virus Killers and Killer T Cells
Mammals like us are large, complex, slow-reproducing life forms thatare subject to parasitism by simpler, rapidly dividing (and mutating)organisms. Through evolutionary time, this need to counter infectionhas led to the evolution of innate immune mechanisms that arecommon to many species, and to the extraordinarily specific, adaptiveimmune system that is characteristic of higher vertebrates.Replicating only in living cells, the viruses are obligate intracellularparasites that throw up two types of challenges for immune control. Infree form, the viruses must in some way transit via the air, throughprotective mucus layers (or in the blood) to access, then enter, thebody cells that will support their growth. At that stage, they arevulnerable to attack by secreted antibodies that bind, in the main, toconformed (tertiary) structures on surface glycoproteins. Antibodyimmunity is the basis of all successful vaccines to date. Then, if a virushas succeeded in bypassing antibody control, there's the need toeliminate the infected cells that serve as "factories" to produce newvirus particles and propagate the disease process. That's the role of the CD8+ or "killer" T cells (T Cells), that are targeted to modified (byvirus peptide) transplantation or major histocompatibility complex(MHC) molecules on the surface of infected cells.With potentially lethal pathogens, it is this interplay between thekinetics of virus spread on the one hand, and immunity on the other,that determines the fate of the infected individual.
obel Prize winner to speak on virus killers
By Erika L. Martinez
June 5, 2008
Nobel Prize winner Peter Doherty will talk about potentially pandemic virus
infections and tools society has to combat them during a Director’s Colloquium
this morning at the Laboratory.
The talk, “Virus Killers and T Cells,” will include qu
antitative and qualitativeanalysis of the influenza virus-
specific CD8+ “killer” T cell response in mouse
model systems. The complexity of these experimental systems also will bediscussed.The talk begins at 10:30 a.m. in the Physics Building Auditorium and is open toall Laboratory employees. The talk also will be shown on LABNET Channel 9 andon desktop computers using Real Media Stream or IPTV technology.
A cytotoxic T cell (also known as CTL) belongs to a sub-group of T lymphocytes -- a type of white blood cell. They kill cells that are infected with viruses or otherpathogens, or are otherwise damaged or dysfunctional.Doherty won the Nobel Prize in Physiology (medicine) in 1996 with Swisscolleague Rolf Zinkernagel for their discovery of how the immune systemrecognizes virus-infected cells. He was Australian of the Year in 1997 and has
since been commuting between St Jude Children’s Research Hospital in
Memphis, Tennessee, and the Department of Microbiology and Immunology atthe University of Melbourne. Doherty's research is mainly in the area of defenseagainst viruses. He also has written several books.
Cytotoxic T cell
Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper"
CD4+ cells.
A
cytotoxic T cell
(also known as
T
C
, CTL, T-Killer cell, cytolytic T cell, CD8+ T-cells or
killer T cell
) belongs to a sub-group of T lymphocytes (a type of white
blood cell)that are capable of inducing the deathof infected somatic or tumor cells; they kill cells that are infected with viruses (or
other pathogens), or are otherwise damaged or dysfunctional. Most cytotoxic T
cells express T-cell receptors (TCRs) that can recognize a
specific antigenic peptide bound to Class I MHC molecules, present on all
nucleated cells, and a glycoprotein called CD8,which is attracted to non-variable
portions of the Class I MHC molecule. The affinity between CD8 and the MHC
molecule keeps the T
C
cell and the target cell bound closely together duringantigen-specific activation.
CD8+ T cells
are recognized as T
C
cells once theybecome activated and are generally classified as having a pre-defined cytotoxicrole within the immune system.
Effector functions
When exposed to infected/dysfunctional somatic cells, T
C
cells release thecytotoxins perforin,granzymes, and granulysin.Perforin forms pores (aqueous
channels) in the target cell'splasma membrane allowing granzymes,types
of serine proteases that cleave at aspartate residues in the substrate, to enter the
target cell, which then activate a series of cysteine proteases,the caspasecascade, that eventually lead to apoptosis (programed cell death). A
second way to induce apoptosis is via cell-surface interactions between theT
C
and the infected cell. When a T
C
(Apo1)(CD95)molecules expressed on the target cell. However, this Fas-Fas ligand interactionis thought to be more important to the disposal of unwanted Tlymphocytes during their development or to the lytic activity of certain T
H
cellsthan it is to the cytolytic activity of T
C
effector cells. Engagement of Fas with FasLallows for recruitment of the death-induced silencing complex (DISC). The Fas-associated death domain (FADD) translocates with the DISC, allowingrecruitment of procaspases 8 and 10. These caspases then activate the effectorcaspases 3, 6, and 7, leading to cleavage of death substrates such as lamin A,lamin B1, lamin B2, PARP (poly-ADP ribose polymerase), and DNAPK (DNA-activated protein kinase). The final result is apoptosis of the cell that expressedFas.