A Therapeutic Tonic for Helpless, Exhausted
Killers
by Jermery Cherfas
Biology Top Ten
Papers
Rank
Papers
Cites Jul-Aug
07
Rank
May-Jun 07
1
D. Altshuler, et al. (Int.’l HapMap
Consortium), "A haplotype map of the human
genome,"Nature, 437(7063): 1299-1320, 27
October 2005. [63 institutions worldwide] *977UQ
69
1
2
E. Bettelli, et al., "Reciprocal
developmental pathways for the generation of pathogenic
effector TH17 and regulatory T cells,"Nature, 441(7090): 235-8, 11 May 2006. [Harvard
Med. Sch., Boston, MA] *040YP
40
2
3
A.-C. Gavin, et al., "Proteome survey
reveals modularity of the yeast cell machinery,"Nature, 440(7084): 631-6, 30 March 2006. [Cellzome
AG, Heidelberg, Germany; EMBL, Heidelberg; MPI-MG, Berlin,
Germany; Austrian Acad. Sci., Vienna] *026OY
30
6
4
M. Veldhoen, et al., "TGFß in the
context of an inflammatory cytokine milieu supports de novo
differentiation of IL-17-producing T cells,"Immunity, 24(2): 179-89, February 2006. [MRC Natl.
Inst. Med. Res., London, U.K.; Howard Hughes Med. Inst., U.
Calif., San Francisco] *014KN
29
5
5
N.J. Krogan, et al., "Global landscape of
protein complexes in the yeast Saccharomyces
cerevisiae,"Nature, 440(7084):
637-43, 30 March 2006. [10 institutions worldwide] *026OY
29
†
6
P.R. Mangan, et al., "Transforming growth
factor-ß induces development of the TH17
lineage,"Nature, 441(7090): 231-4, 11
May 2006. [U. Alabama, Birmingham; NIDCD, NIH, Bethesda,
MD] *040YP
27
†
7
A. Cimmino, et al., "miR-15 and
miR-16 induce apoptosis by targeting
BCL2,"PNAS, 102(39): 13944-9, 27
September 2005. [Ohio St. U., Columbus; U. Ferrara, Italy;
Inst. Naz. Ric. Cancro, Genoa, Italy; U. Calif., San Diego]
*969KB
27
†
8
M. Margulies, et al., "Genome sequencing
in microfabricated high-density picolitre
reactors,"Nature,
437(7057): 376-80, 15 September 2005. [Life Sciences Corp.,
Branford, CT; U. Calif., Berkeley; Rockefeller U., New
York, NY; Rothberg Inst., Guilford, CT] *964AS
25
3
9
D.K. Pokholok, et al., "Genome-wide map of
nucleosome acetylation and methylation in yeast,"Cell, 122(4): 517-27, 26 August 2005. [Whitehead
Inst., Cambridge, MA; MIT, Cambridge] *959YI
24
†
10
D.L. Barber, et al., "Restoring function
in exhausted CD8 T cells during chronic viral
infection,"Nature, 439(7077): 682-7, 9
February 2006. [5 U.S. institutions] *010KH
Most viral infections the immune system deals with swiftly and effectively.
Some elude destruction and go on to establish a chronic infection. The
paper at #10 identifies the main difference between the two types of
infection and suggests a therapeutic approach that could help the body to
clear persistent viral infections such as hepatitis B,
hepatitis C, and
HIV.
Rafi Ahmed and his colleagues at Emory University in Atlanta, Georgia, and
elsewhere made use of lymphocytic choriomeningitis virus (LCMV), which can
go either way, acute or chronic, in mice. One viral strain, the Armstrong
strain, is cleared within a week. Another, known as clone 13, differs from
Armstrong at only two amino acids across its entire genome, and yet results
in a chronic infection.
Ahmed showed almost a decade ago that the primary difference is that in
mice with a chronic infection the CD8 T cells no longer have the ability to
kill infected cells. In mice that have recovered from an acute infection
the CD8 T cells "remember" the virus and are a vital part of acquired
immunity. This paper identifies the basis of T-cell ineffectiveness and
delivers a pick-me-up to exhausted CD8 T cells.
The differences between Armstrong strain and clone 13 do not affect any of
the regions that stimulate T-cell recognition of LCMV; the main difference
is in the end result. Harvesting T-cells specific to LCMV from chronic and
acute cases, Ahmed's group used a genome-wide microarray analysis to look
for differences between the effective T memory cells and the exhausted T
cells.
As an aside, it's worth noting that the use of once-miraculous DNA-chip
technology (see, for example, Science Watch, 12[4]: 8,
July/August 2001) now merits a single sentence. Exhausted cells,
it turned out, expressed vastly more of a protein called PD-1, for
programmed death 1. Functional memory T cells did not express detectable
levels of PD-1.
Looking at the time course of infection in more detail, the researchers
noted that both strains elicited the expression of PD-1 early on, but in
the acute infection this was rapidly down-regulated, while in the chronic
infection expression remained high. PD-1 recognizes two ligands, PD-L1 and
PD-L2. In chronically infected mice, PD-L1 is also expressed at high
levels, especially on virally infected cells. All of which suggests that
PD-1 and its ligand PD-L1 are involved in regulating CD8 T-cell function.
An antibody that blocked PD-1's access to PD-L1 resulted in a greater
number of T cells specific to LCMV, and those cells were more capable of
killing infected host cells. Treated mice cleared the virus from their
systems, remained healthy, and showed no signs of the disease. CD8 killer
cells normally derive a certain amount of support from CD4 helper cells,
but even in mice without CD4 helper cells, blocking PD-L1 promoted the
growth of CD8 cells and restored their potency.
Just to be sure, Ahmed and his colleagues also gave chronically infected
mice an antibody to PD-1 itself. This worked too, but not as effectively as
blocking PD-1's target. It seems that the interaction between PD-1 and
PD-L1 is what suppresses the CD8 cell's ability to proliferate and target
infected cells. Interrupt the interaction, even relatively briefly, and you
reinvigorate the exhausted CD8 cells for several weeks.
As a final test, Ahmed and his colleagues infected mice that lack the PD-L1
gene. They responded just like wild-type mice when infected with the
Armstrong strain, producing a normal CD8 T cell response that cleared the
acute infection and resulted in memory T cells specific to the virus. Mice
infected with strain 13, however, died as a result of immunopathologic
damage.
This suggests that down-regulating PD-1 actually protects the animal from
its own immune response, for which there is other evidence too. Some
viruses and viral strains have evolved to take advantage of this and
establish a chronic infection.
Of course the big news in this paper is not the nitty-gritty detail but the
discovery that blocking PD-L1 revives exhausted CD8 cells. This raises two
big questions. First, will it work in important chronic human viral
infections? Yes, at least for HIV, where there is also apparently a
difference in PD-1 between patients in whom the disease progresses normally
and those who are "long-term nonprogressors." (See G.J. Freeman, et
al., J. Exp. Med., 2006, DOI:10.1084/jem.20061800; and J.
Zhang, et al., Blood, 2007,
DOI:10.1182/blood-2006-09-044826.) Secondly, vaccines do nothing to help
patients deal with chronic infections, probably because their T cells are
exhausted. Could blocking PD-L1 enhance the potential of therapeutic
vaccines? No word on that. Yet.
Dr. Jeremy Cherfas is Science Writer at Bioversity International,
Rome, Italy.