The role of IL-7 in lymphopenia and bystander apoptosis during HIV-1 infection
Author: Fluur, Caroline
Date: 2007-02-09
Location: Föreläsningssalen vid Institutionen för Mikrobiologi, Tumör och Cellbiologi (MTC), Theorellsväg 1, Karolinska Institutet
Time: 09.00
Department: Institutionen för mikrobiologi, tumör- och cellbiologi / Department of Microbiology, Tumor and Cell Biology
View/ Open:
thesis.pdf (827.9Kb)
Abstract
The concentration of interleukin-7 (IL-7) in human serum is elevated in
various clinical conditions associated with lymphopenia. IL-7 is an
essential factor for T cell differentiation and survival, and high IL-7
concentration has been proposed to represent a homeostatic response to T
cell depletion, which may accelerate thymic output and promote T cell
regeneration. During HIV-1 infection, however, high levels of IL-7 are
correlated with CD4+ T cell depletion and appear not to be beneficial to
rescue the diminishing T cell pool.
In order to further understand the impact of T cell numbers on serum IL-7
levels at different clinical stages of HIV-1 infection we investigated
specimens from HIV-1 infected patients during primary and chronic
infection and in long term non-progressors (LTNPs). In patients with
primary HIV-1 infection, CD4+ and CD8+ T cell counts showed no
correlation with the high IL-7 levels found in these patients; however
the significant association seen between IL-7 and total CD3+ T cell
counts may reflect an effect of lymphopenia on the increased IL-7 level,
as previously reported in chronic HIV-1 infection. We also studied IL-7
levels in LTNPs, characterized by CD4+ T cell counts above 500 cells/μl
and control of viral replication for 7 to 10 years without ART. Some of
the LTNPs individuals progressed to a symptomatic phase of HIV-1
infection and, interestingly, we observed that these individuals showed a
higher IL-7 level before progression as compared to the LTNPs that
maintained high CD4+ T cell counts and virological control.
We asked the question on whether positive effects of IL-7 on survival and
homeostatic proliferation of T cells might be severely impaired in
HIV-infected individuals due to IL-7Rα down-regulation. Thus the
frequency of IL-7Rα- T cells in HIV-1 infected patients was studied in
relation to CD4 Tcell counts, IL-7 concentration and expression in
different T-cell populations. Down-regulation of IL-7Rα on T cells
correlated with depletion of CD4 T cells (P < 0.001) and also with
increased concentration of serum IL-7 (P < 0.05). Particularly, T cells
with memory phenotype showed a decreased IL-7Rα expression in association
with CD28 down-regulation. Thus, IL-7Rα downregulation and
differentiation towards a CD28- memory phenotype in response to chronic
activation may lead to an overall decrease of IL-7 mediated survival
within the peripheral T-cell pool.
The loss of CD4+ T cells during HIV-1 infection is not entirely the cause
of direct infection of these cells, but is also due to bystander
apoptosis where uninfected cells are predisposed to death inducing
signals. As elevated IL-7 levels occur in HIV-infected individuals in
addition to high Fas expression on T cells and increased sensitivity to
Fas-induced apoptosis, we analyzed whether IL-7 has a regulatory role in
Fas-mediated T cell apoptosis. We showed that IL-7 up-regulates in vitro
Fas expression on naïve and memory T cells through a mechanism that
involves translocation of Fas molecules from intracellular compartments
to the cell membrane. The role of IL-7 in Fas upregulation in vivo was
verified in IL-7 treated macaques. In addition IL-7 treatment primed T
cells for Fas-induced apoptosis in vitro and serum IL-7 levels correlated
with the sensitivity of T cells to Fas-induced apoptosis in HIV-infected
individuals. Our data suggest that elevated IL-7 levels associated with
HIV-1 infection, might participate in the increased sensitivity of T
cells for activation-induced apoptosis.
Alteration of receptor-mediated apoptosis is not limited to HIV-1
infection, but is also present in other infections including
Leishmaniasis. Leishmaniasis infections often occur in areas of high
HIV-1 prevalence. During Cutaneous Leishmaniasis (CL), caused by L. Major
infection, there is a chronic inflammation process that leads to killing
of the non-infected keratinocytes in the epidermis followed by
disfiguring scar formations. Our studies showed that the expression of
Fas, TRAIL-R2 and TRAIL is increased on keratinocytes upon exposure to
supernatant from Leishmania infected PBMC cultures and in diseased skin
from patients with CL. The expression of death receptors also renders the
keratinocytes more sensitive to apoptosis and they can die through a
bystander effect due to infiltrating immune cells expressing death
ligands. Blocking Fas and TRAIL in vitro inhibits, to a great extent,
apoptosis occurring in the experimental procedure.
List of papers:
I. Fluur C, Rethi B, Thang PH, Vivar N, Mowafi F, Lopalco L, Uberti Foppa C, Karlsson A, Tambussi G, Chiodi F. (2007). "Relationship of interleukin-7 levels and lymphopenia in early and late stages of HIV infection." (Submitted)
II. Rethi B, Fluur C, Atlas A, Krzyzowska M, Mowafi F, Grutzmeier S, De Milito A, Bellocco R, Falk KI, Rajnavolgyi E, Chiodi F. (2005). "Loss of IL-7Ralpha is associated with CD4 T-cell depletion, high interleukin-7 levels and CD28 down-regulation in HIV infected patients." AIDS 19(18): 2077-86
Pubmed
III. Fluur C, De Milito A, Fry TJ, Eidsmo L, Atlas A, Federici C, Matarrese P, Logozzi A, Rajnavölgyi E, Mackall CL, Fais S, Chiodi F, Rethi B. (2007). "Possible role for IL-7 in Fas mediated T cell apoptosis during HIV-1 infection." (Submitted)
IV. Eidsmo L, Fluur C, Rethi B, Eriksson Ygberg S, Ruffin N, De Milito A, Akuffo H, Chiodi F. (2007). "FasL and TRAIL Induce Epidermal Apoptosis and Skin Ulceration Upon Exposure to Leishmania major." Am J Pathol 170(1): 227-39
Pubmed
I. Fluur C, Rethi B, Thang PH, Vivar N, Mowafi F, Lopalco L, Uberti Foppa C, Karlsson A, Tambussi G, Chiodi F. (2007). "Relationship of interleukin-7 levels and lymphopenia in early and late stages of HIV infection." (Submitted)
II. Rethi B, Fluur C, Atlas A, Krzyzowska M, Mowafi F, Grutzmeier S, De Milito A, Bellocco R, Falk KI, Rajnavolgyi E, Chiodi F. (2005). "Loss of IL-7Ralpha is associated with CD4 T-cell depletion, high interleukin-7 levels and CD28 down-regulation in HIV infected patients." AIDS 19(18): 2077-86
Pubmed
III. Fluur C, De Milito A, Fry TJ, Eidsmo L, Atlas A, Federici C, Matarrese P, Logozzi A, Rajnavölgyi E, Mackall CL, Fais S, Chiodi F, Rethi B. (2007). "Possible role for IL-7 in Fas mediated T cell apoptosis during HIV-1 infection." (Submitted)
IV. Eidsmo L, Fluur C, Rethi B, Eriksson Ygberg S, Ruffin N, De Milito A, Akuffo H, Chiodi F. (2007). "FasL and TRAIL Induce Epidermal Apoptosis and Skin Ulceration Upon Exposure to Leishmania major." Am J Pathol 170(1): 227-39
Pubmed
Issue date: 2007-01-19
Rights:
Publication year: 2007
ISBN: 978-91-7357-074-9
Statistics
Total Visits
Views | |
---|---|
The ...(legacy) | 633 |
The ... | 99 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
The ... | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 435 |
thesis.pdf | 118 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 323 |
China | 72 |
Sweden | 59 |
Germany | 46 |
South Korea | 20 |
Finland | 14 |
Russia | 9 |
United Kingdom | 7 |
Ireland | 7 |
Japan | 7 |
Top cities views
Views | |
---|---|
Beijing | 48 |
Sunnyvale | 27 |
Romeo | 21 |
Kiez | 20 |
Seoul | 14 |
Helsinki | 8 |
Ashburn | 7 |
Dublin | 7 |
University Park | 7 |
Ballerup | 6 |