CD8+ive T cell death in HIV infection

Laszlo Radvanyi radvanyi at oci.utoronto.ca
Mon Mar 13 02:55:00 EST 1995


     The question of the role of CD8 T cells in HIV immunopathology is 
becoming increasingly important in understanding progression to 
full-blown AIDS.  The issue of CD8 cells is also a controversial issue with 
respect to disease progression.  Some studies have shown that infected 
individuals able to mount a powerful enough cytotoxic 
T-cell-mediated immune response against specific viral epitopes 
(assayable in vitro) are protected against progression to full blown 
AIDs.  The recent discovery of a cohort of prostitutes from Africa as 
well as documented cases in North America showing enhanced cell-mediated 
immune responses against HIV are examples.  However, other studies point 
to a possible destructive action of cell-mediated immune reponses in 
controlling HIV infection.  For example a study published in 1993 by a 
group from McMaster University under Ken Rosenthal (published in J. Exp. 
Med.) showed that CD8+ive T cells from HIV-infected (asymptomatic) 
individuals killed bystander CD4+ T cells both syngeneic and allogeneic 
from either normal or HIV-infected individuals.  It is not known whether 
the cells killed in the HIV+ group were actually infected; however, the 
killing of normal CD4+ T cells from non-infected individuals points to 
some other mechanism playing a role in this killing phenomenon which may 
or may not be mediated by antigen recognition.  This is where the 
question of apoptosis regulation in the immune system and its role in HIV 
infection comes to the foreground.

     A recent study published in Nature Medicine (Vol. 1 pp. 129-134) has 
shown that the most if not all T cell death (both CD4+ and CD8+) occured 
in non-HIV-infected cells in lymph nodes of HIV-infected children as well 
as SIV-infected macaques.  So what is going on?
     Well, HIV like other chronic viral infections (e.g., EBV), leads to 
chronic activation of the immune system.  In fact, there is evidence of 
superantigen-like effects mediated by HIV activating entire subsets of 
CD4 and CD8 T cells resricted by only the Vbeta element of the TCR.  Immune 
activation also has a number of perilous consequences for T cells
themselves- they become highly susceptible to cell death through 
apoptosis.  A number of interacting mechanisms to play a role here.  
First, activated T cells in cell cycle are susceptible to activation-induced 
cell death, especially CD8+ T cells.  Studies in our lab have shown that 
T cells entering S phase are acutely susceptible to TCR-mediated cell 
death.  Moreover, it has been shown that T cells from HIV infected and 
EBV infected individuals have low levels of expression of a well known 
anti-apoptotic gene called bcl-2 (published in J. Exp. Med. in 1992 by 
George Janossy's group in London UK).  Activated T cells, especially CD8+ 
T cells also express the fas antigen and high levels of fas-ligand.  
Ligation of fas on activated T cells triggers apoptosis.  
     All these aforementioned factors/events, coupled with the increased 
levels of inflammatory cytokines (IL-1, TNF) in HIV infected patients, 
seem to be the recipe for disaster which abrogates an effective immune 
response and allows the virus to keep on replicating.  In essence, the 
immune system may burn itself out and be unable to generate memory T 
cells due to the overactivation of effector (Th1) cells causing widespread 
apoptosis.
     Thus the death of CD8+ cells could be the result of chronic 
overactivation downregulating bcl-2.  Fas ligand triggered apoptosis in 
overactivated/chronically activated T cells.  Interestingly, here T cells 
may also kill each other via a so-called fratricidal process.  Incidentally, 
this form of cell death has been shown to be inhibited by 
overexpression of bcl-2.  This may explain the killing of T cells from 
normal individuals by CD8+ T cells from HIV-infected patients.  
However, further experimentation needs to be done.
     In conclusion, death of the cell mediated arm of the immune 
response against HIV due to these apoptotic mechanisms may trigger the 
inability to form a Th1-type memory.  Instead, cells that proliferate 
less in response to infection (cycle slowly and don't upregulate fas 
very well) may survive.  These are the Th2-type cells that mediate 
weaker antibody-mediated responses.  Thus, a Th2-type memory may dominate 
which is unable to cope with the rapid replication of the HIV virus 
after the Th1 cells die out.  Interestingly, a recent paper  
(International Immunology, this year) has shown that Th2 T cell lines are 
refractory to activation-induced T-cell death and this was also 
correlated to decreased expression of fas antigen on these cells.

    I hope these comments have helped.  Any further 
comments/questions/ideas welcome.

Laszlo Radvanyi
Ontario Cancer Institute, 
Princess Margaret Hospital
Toronto Ontario, M4X 1K9
tel: 924-0671 ext. 4994
fax: 926-6529
e-mail: radvanyi at oci.utoronto.ca    



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