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Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection.

Okoye A, Meier-Schellersheim M, Brenchley JM, Hagen SI, Walker JM, Rohankhedkar M, Lum R, Edgar JB, Planer SL, Legasse A, Sylwester AW, Piatak M, Lifson JD, Maino VC, Sodora DL, Douek DC, Axthelm MK, Grossman Z, Picker LJ - J. Exp. Med. (2007)

Bottom Line: Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial.We further show that due to persistent immune activation, effector site CD4(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors.The instability of effector site CD4(+) T(EM) cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5(-) CD4(+) T(CM) cells.

View Article: PubMed Central - PubMed

Affiliation: Vaccine and Gene Therapy Institute, Department of Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., USA.

ABSTRACT
Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4(+) CCR5(+) effector-memory T (T(EM)) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4(+) memory T cell proliferation appears to prevent collapse of effector site CD4(+) T(EM) cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4(+) T(EM) cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors. The instability of effector site CD4(+) T(EM) cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5(-) CD4(+) T(CM) cells. These data suggest that although CD4(+) T(EM) cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4(+) T(CM) cells.

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Related in: MedlinePlus

The descent to AIDS: decreasing numbers and changing proportions of CD4+ memory T cell populations in chronic SIVmac239 infection. The figure schematically illustrates the progressive decline in the regeneration of long-lived TCM cells and, consequently, in the production of short-lived, tissue-seeking TEM cells. The TCM cell compartment consists of TCM cells in secondary lymphoid tissues and recirculating in the blood. The TEM cell compartment represents cells resident in extra-lymphoid effector sites. Estimated populations include: (a) recently divided (Ki-67+) cells (cells that have been in S-phase of the cell cycle in the preceding week), (b) short-lived cells (Ki-67− cells destined to die or resume division in <2–3 wk), (c) long-lived cells (Ki-67− cells destined to live >3 wk without cell division), and (d) dying cells (either apoptosis or direct viral destruction). The left to right horizontal arrows indicate the relative rate of production and effector site emigration of TEM cells. The semicircular arrow adjacent to the TCM cell compartment indicates the relative efficiency of TCM cell regeneration (note that proliferating TCM cells provide the substrate for both TCM cell regeneration and TEM cell production). (A) Preinfection baseline. Both TCM and TEM cell compartments include relatively large proportions of long-lived cells. (B) Asymptomatic chronic phase—mid-course. Both compartments have experienced dramatic acute-phase depletion (TEM > TCM) and have established a quasi-stable steady-state with substantially reduced cell numbers, especially of long-lived cells, and increased proliferation and death rates. Both TCM cell regeneration and TEM cell production are reduced severalfold from baseline, despite the increased proportion of proliferating TCM cells, but this fractional increase in a reduced compartment is still sufficient to maintain predominantly short-lived TEM cell populations above the immune deficiency threshold. (C) End-stage chronic phase—AIDS onset. Progressive decline in the TCM cell compartment has reduced TEM cell production and delivery to effector sites below the minimum necessary to maintain TEM cell populations above threshold, leaving these sites increasingly susceptible to opportunistic infection.
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fig8: The descent to AIDS: decreasing numbers and changing proportions of CD4+ memory T cell populations in chronic SIVmac239 infection. The figure schematically illustrates the progressive decline in the regeneration of long-lived TCM cells and, consequently, in the production of short-lived, tissue-seeking TEM cells. The TCM cell compartment consists of TCM cells in secondary lymphoid tissues and recirculating in the blood. The TEM cell compartment represents cells resident in extra-lymphoid effector sites. Estimated populations include: (a) recently divided (Ki-67+) cells (cells that have been in S-phase of the cell cycle in the preceding week), (b) short-lived cells (Ki-67− cells destined to die or resume division in <2–3 wk), (c) long-lived cells (Ki-67− cells destined to live >3 wk without cell division), and (d) dying cells (either apoptosis or direct viral destruction). The left to right horizontal arrows indicate the relative rate of production and effector site emigration of TEM cells. The semicircular arrow adjacent to the TCM cell compartment indicates the relative efficiency of TCM cell regeneration (note that proliferating TCM cells provide the substrate for both TCM cell regeneration and TEM cell production). (A) Preinfection baseline. Both TCM and TEM cell compartments include relatively large proportions of long-lived cells. (B) Asymptomatic chronic phase—mid-course. Both compartments have experienced dramatic acute-phase depletion (TEM > TCM) and have established a quasi-stable steady-state with substantially reduced cell numbers, especially of long-lived cells, and increased proliferation and death rates. Both TCM cell regeneration and TEM cell production are reduced severalfold from baseline, despite the increased proportion of proliferating TCM cells, but this fractional increase in a reduced compartment is still sufficient to maintain predominantly short-lived TEM cell populations above the immune deficiency threshold. (C) End-stage chronic phase—AIDS onset. Progressive decline in the TCM cell compartment has reduced TEM cell production and delivery to effector sites below the minimum necessary to maintain TEM cell populations above threshold, leaving these sites increasingly susceptible to opportunistic infection.

Mentions: BrdU labeling of chronically SIVmac239-infected RMs was then used to explore the dynamics of pulmonary CD4+ TEM cells and provide insights into the mechanisms underlying their progressive decline. We found that this population is largely comprised of short-lived nonreplicating cells and consequently is highly dependent on the continuous emigration of recently divided TEM cells from the blood. Notably, pulmonary CD8+ TEM cells manifested similar kinetic properties suggesting that (a) the short life span of the CD4+ TEM cells in BAL was not attributable to direct viral-mediated destruction, but rather was likely a result of chronic immune activation (12, 34), and (b) that the progressive decline in CD4+ TEM cells was determined elsewhere, probably by factors controlling the supply of these cells to extra-lymphoid effector sites. In keeping with the latter hypothesis, we found that absolute numbers of proliferating or recently divided CD4+, but not CD8+, memory T cells in the blood progressively declined in chronic SIVmac239 infection (but not in attenuated SIVmac239(Δnef) infection). The fraction of these proliferating or recently divided CD4+ memory cells exhibiting TEM cell differentiation (i.e., the immediate precursors to extra-lymphoid site TEM cells) was considerably diminished in progressive infection by direct virus-mediated destruction (Fig. 6), but, importantly, this fraction did not appear to change over the course of chronic infection. Collectively, these findings strongly suggested that a progressive, systemic decline of the proliferating CD4+ TCM cell compartment resulted in a progressively diminished substrate for CD4+ TEM cell differentiation. This in turn reduced CD4+ TEM cell production and effector site emigration, leading to decreasing effector site CD4+ TEM cell populations and ultimately (when the latter fell below threshold) to AIDS (Fig. 8).


Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection.

Okoye A, Meier-Schellersheim M, Brenchley JM, Hagen SI, Walker JM, Rohankhedkar M, Lum R, Edgar JB, Planer SL, Legasse A, Sylwester AW, Piatak M, Lifson JD, Maino VC, Sodora DL, Douek DC, Axthelm MK, Grossman Z, Picker LJ - J. Exp. Med. (2007)

The descent to AIDS: decreasing numbers and changing proportions of CD4+ memory T cell populations in chronic SIVmac239 infection. The figure schematically illustrates the progressive decline in the regeneration of long-lived TCM cells and, consequently, in the production of short-lived, tissue-seeking TEM cells. The TCM cell compartment consists of TCM cells in secondary lymphoid tissues and recirculating in the blood. The TEM cell compartment represents cells resident in extra-lymphoid effector sites. Estimated populations include: (a) recently divided (Ki-67+) cells (cells that have been in S-phase of the cell cycle in the preceding week), (b) short-lived cells (Ki-67− cells destined to die or resume division in <2–3 wk), (c) long-lived cells (Ki-67− cells destined to live >3 wk without cell division), and (d) dying cells (either apoptosis or direct viral destruction). The left to right horizontal arrows indicate the relative rate of production and effector site emigration of TEM cells. The semicircular arrow adjacent to the TCM cell compartment indicates the relative efficiency of TCM cell regeneration (note that proliferating TCM cells provide the substrate for both TCM cell regeneration and TEM cell production). (A) Preinfection baseline. Both TCM and TEM cell compartments include relatively large proportions of long-lived cells. (B) Asymptomatic chronic phase—mid-course. Both compartments have experienced dramatic acute-phase depletion (TEM > TCM) and have established a quasi-stable steady-state with substantially reduced cell numbers, especially of long-lived cells, and increased proliferation and death rates. Both TCM cell regeneration and TEM cell production are reduced severalfold from baseline, despite the increased proportion of proliferating TCM cells, but this fractional increase in a reduced compartment is still sufficient to maintain predominantly short-lived TEM cell populations above the immune deficiency threshold. (C) End-stage chronic phase—AIDS onset. Progressive decline in the TCM cell compartment has reduced TEM cell production and delivery to effector sites below the minimum necessary to maintain TEM cell populations above threshold, leaving these sites increasingly susceptible to opportunistic infection.
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Related In: Results  -  Collection

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fig8: The descent to AIDS: decreasing numbers and changing proportions of CD4+ memory T cell populations in chronic SIVmac239 infection. The figure schematically illustrates the progressive decline in the regeneration of long-lived TCM cells and, consequently, in the production of short-lived, tissue-seeking TEM cells. The TCM cell compartment consists of TCM cells in secondary lymphoid tissues and recirculating in the blood. The TEM cell compartment represents cells resident in extra-lymphoid effector sites. Estimated populations include: (a) recently divided (Ki-67+) cells (cells that have been in S-phase of the cell cycle in the preceding week), (b) short-lived cells (Ki-67− cells destined to die or resume division in <2–3 wk), (c) long-lived cells (Ki-67− cells destined to live >3 wk without cell division), and (d) dying cells (either apoptosis or direct viral destruction). The left to right horizontal arrows indicate the relative rate of production and effector site emigration of TEM cells. The semicircular arrow adjacent to the TCM cell compartment indicates the relative efficiency of TCM cell regeneration (note that proliferating TCM cells provide the substrate for both TCM cell regeneration and TEM cell production). (A) Preinfection baseline. Both TCM and TEM cell compartments include relatively large proportions of long-lived cells. (B) Asymptomatic chronic phase—mid-course. Both compartments have experienced dramatic acute-phase depletion (TEM > TCM) and have established a quasi-stable steady-state with substantially reduced cell numbers, especially of long-lived cells, and increased proliferation and death rates. Both TCM cell regeneration and TEM cell production are reduced severalfold from baseline, despite the increased proportion of proliferating TCM cells, but this fractional increase in a reduced compartment is still sufficient to maintain predominantly short-lived TEM cell populations above the immune deficiency threshold. (C) End-stage chronic phase—AIDS onset. Progressive decline in the TCM cell compartment has reduced TEM cell production and delivery to effector sites below the minimum necessary to maintain TEM cell populations above threshold, leaving these sites increasingly susceptible to opportunistic infection.
Mentions: BrdU labeling of chronically SIVmac239-infected RMs was then used to explore the dynamics of pulmonary CD4+ TEM cells and provide insights into the mechanisms underlying their progressive decline. We found that this population is largely comprised of short-lived nonreplicating cells and consequently is highly dependent on the continuous emigration of recently divided TEM cells from the blood. Notably, pulmonary CD8+ TEM cells manifested similar kinetic properties suggesting that (a) the short life span of the CD4+ TEM cells in BAL was not attributable to direct viral-mediated destruction, but rather was likely a result of chronic immune activation (12, 34), and (b) that the progressive decline in CD4+ TEM cells was determined elsewhere, probably by factors controlling the supply of these cells to extra-lymphoid effector sites. In keeping with the latter hypothesis, we found that absolute numbers of proliferating or recently divided CD4+, but not CD8+, memory T cells in the blood progressively declined in chronic SIVmac239 infection (but not in attenuated SIVmac239(Δnef) infection). The fraction of these proliferating or recently divided CD4+ memory cells exhibiting TEM cell differentiation (i.e., the immediate precursors to extra-lymphoid site TEM cells) was considerably diminished in progressive infection by direct virus-mediated destruction (Fig. 6), but, importantly, this fraction did not appear to change over the course of chronic infection. Collectively, these findings strongly suggested that a progressive, systemic decline of the proliferating CD4+ TCM cell compartment resulted in a progressively diminished substrate for CD4+ TEM cell differentiation. This in turn reduced CD4+ TEM cell production and effector site emigration, leading to decreasing effector site CD4+ TEM cell populations and ultimately (when the latter fell below threshold) to AIDS (Fig. 8).

Bottom Line: Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial.We further show that due to persistent immune activation, effector site CD4(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors.The instability of effector site CD4(+) T(EM) cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5(-) CD4(+) T(CM) cells.

View Article: PubMed Central - PubMed

Affiliation: Vaccine and Gene Therapy Institute, Department of Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., USA.

ABSTRACT
Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4(+) CCR5(+) effector-memory T (T(EM)) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4(+) memory T cell proliferation appears to prevent collapse of effector site CD4(+) T(EM) cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4(+) T(EM) cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors. The instability of effector site CD4(+) T(EM) cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5(-) CD4(+) T(CM) cells. These data suggest that although CD4(+) T(EM) cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4(+) T(CM) cells.

Show MeSH
Related in: MedlinePlus