Attrition of bystander CD8 T cells during virus-induced T-cell and interferon responses - PubMed (original) (raw)

Attrition of bystander CD8 T cells during virus-induced T-cell and interferon responses

J M McNally et al. J Virol. 2001 Jul.

Abstract

Experiments designed to distinguish virus-specific from non-virus-specific T cells showed that bystander T cells underwent apoptosis and substantial attrition in the wake of a strong T-cell response. Memory CD8 T cells (CD8(+) CD44(hi)) were most affected. During acute viral infection, transgenic T cells that were clearly defined as non-virus specific decreased in number and showed an increase in apoptosis. Also, use of lymphocytic choriomeningitis virus (LCMV) carrier mice, which lack LCMV-specific T cells, showed a significant decline in non-virus-specific memory CD8 T cells that correlated to an increase in apoptosis in response to the proliferation of adoptively transferred virus-specific T cells. Attrition of T cells early during infection correlated with the alpha/beta interferon (IFN-alpha/beta) peak, and the IFN inducer poly(I:C) caused apoptosis and attrition of CD8(+) CD44(hi) T cells in normal mice but not in IFN-alpha/beta receptor-deficient mice. Apoptotic attrition of bystander T cells may make room for the antigen-specific expansion of T cells during infection and may, in part, account for the loss of T-cell memory that occurs when the host undergoes subsequent infections.

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Figures

FIG. 1

Adoptive transfer of LCMV-immune splenocytes into LCMV carrier mice leads to a reduction in the number of host CD8 T cells and an increase in host T-cell apoptosis. (A) Spleens from LCMV carrier mice (Thy 1.2+), which received an adoptive transfer of 3 × 107 naive or LCMV-immune Thy 1.1+ splenocytes (Thy 1.2−), were stained to determine the proportions of donor and host-derived CD8 T cells 6 days after reconstitution. APC, antigen-presenting cells. (B) Host-derived cells were gated on memory (CD44hi) and naive (CD44lo) phenotypes, and apoptosis of these populations was assessed using annexin V. (C) Light scatter properties of annexin V+ or annexin V− host-derived memory T cells is shown, demonstrating that the annexin V+ population is smaller and more granular than the annexin V− T cells. In all cases, data shown are from an individual mouse in a representative experiment (n = 3).

FIG. 2

Kinetic analysis of CD8+ T cells found in the spleens of mice undergoing an acute LCMV infection. (A) Spleens from LCMV-infected B6 mice were analyzed using flow cytometry to determine the number of memory (CD44hi) or naive (CD44lo) CD8 T cells during the course of the viral infection. Results are expressed as the mean number of cells per spleen ± standard deviation (n = 3 per time point). (B) Annexin staining of memory and naive CD8 T cells from a representative mouse 2 days following LCMV infection. In both panels, gating on CD44hi versus CD44lo cells was determined using the day 9 postinfection time point to include the majority of activated cells. This resulted in a broader definition of CD44hi cells than would occur if day 0 control mice were used for determining the gates. D0, day 0; D2, day 2.

FIG. 3

Poly(I:C) injection leads to a significant decrease in the number of CD8+ CD44hi T cells in the spleen and an increase in their apoptosis. (A) Splenocytes from B6 mice injected with poly(I:C) were stained for CD8, CD44, and B220 expression to determine the number of CD8 T cells (memory [CD44hi] or naive [CD44lo]) and B cells present on days 1 to 3 postinjection. The proportion of annexin V+ cells for these mice is shown in panel B. Data shown are from a representative experiment (n = 5). D0, day 0; D1, day 1; etc. *, P < 0.05, compared to day 0 control.

FIG. 4

Poly(I:C) induces attrition of LCMV-specific memory CD8 T cells. Splenocytes from LCMV-immune mice (see Materials and Methods) were analyzed for expression of CD8 and an MHC tetramer (H-2Db) specific for the LCMV peptide NP396–404. LCMV-immune mice were injected with poly(I:C) and analyzed, as previously described. Representative histograms from an experiment performed twice are shown. D0, day 0; D1, day 1.

FIG. 5

The T-cell repertoire is not permanently altered by poly(I:C) treatment, as determined by FACS analysis and CDR3 length spectratyping. (A and B) Sequentially bled LCMV-immune mice were analyzed following poly(I:C) treatment to determine if any significant changes in the T-cell repertoire took place as a result of the attrition of memory T cells. Although the percentage of CD8 T cells is reduced on day 1 following poly(I:C) injection (A), the proportion of those cells that are Vβ 8.1/8.2+ was not altered (B). ▿, control mice; ●, poly(I:C)-treated mice. (C) The Vβ8.1 T cells were further analyzed for changes in their repertoire using CDR3 length spectratyping. Mice exhibiting the most significant changes in T-cell repertoire for Jβ1.3, Jβ1.6, Jβ1.5, and Jβ2.7 are shown. Even though these mice exhibited the most significant changes of all mice and Jβ's tested, the changes were transient and the mice returned to their original distribution by 8 days after the poly(I:C) treatment. *, change in spectratype. PBLs, peripheral blood lymphocytes; d0 and D0, day 0; d1, day 1; D3, day 3; D8, day 8.

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Attrition of bystander CD8 T cells during virus-induced T-cell and interferon responses - PubMed (original) (raw)