SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination - PubMed (original) (raw)

SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination

Nichole R Klatt et al. Blood. 2011.

Abstract

HIV infection is characterized by immune system dysregulation, including depletion of CD4+ T cells, immune activation, and abnormal B- and T-cell responses. However, the immunologic mechanisms underlying lymphocytic dysfunctionality and whether it is restricted to immune responses against neo antigens, recall antigens, or both is unclear. Here, we immunized SIV-infected and uninfected rhesus macaques to induce immune responses against neo and recall antigens using a Leishmania major polyprotein (MML) vaccine given with poly-ICLC adjuvant. We found that vaccinated SIVuninfected animals induced high frequencies of polyfunctional MML-specific CD4+ T cells. However, in SIV-infected animals, CD4+ T-cell functionality decreased after both neo (P = .0025) and recall (P = .0080) MML vaccination. Furthermore, after SIV infection, the frequency of MML-specific antibody-secreting classic memory B cells was decreased compared with vaccinated, SIV-uninfected animals. Specifically, antibody-secreting classic memory B cells that produced IgA in response to either neo (P = .0221) or recall (P = .0356) MML vaccinations were decreased. Furthermore, we found that T-follicular helper cells, which are essential for priming B cells, are preferentially infected with SIV. These data indicate that SIV infection results in dysfunctional T-cell responses to neo and recall vaccinations, and direct SIV infection of T-follicular helper cells, both of which probably contribute to deficient B-cell responses and, presumably, susceptibility to certain opportunistic infections.

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Figures

Figure 1

Figure 1

Loss of multifunctional MML-specific CD4+ T cells after SIV infection in neo-vaccinated animals. Flow cytometric analysis of MML-specific memory and effector (CD28+CD95+ and CD28−CD95+/−) CD4+ T cells 2 weeks after neo MML vaccinations by production of CD40L, IFNγ, IL-2, TNFα, or a combination. (A) Pie charts represent fraction of cells that have 4 (yellow), 3 (cyan), 2 (blue), or 1 (purple) function(s). P value calculated by partial permutation test. (B) Delineation of the 15 possible cytokine combinations is shown for SIV− (green) and SIV+ (black). Dots represent individual RM responses. (C) Student t test results between SIV− and SIV+ cytokine responses corresponding to panel B. Pink shading represents a significant P value less than .05. (D) Total frequency of cytokine producing memory and effector CD4+ T cells for SIV− (green) and SIV+ (black) in response to MML stimulation. P values represent partial permutation test results (A) or Student t test results (C). MML-specific responses from uninfected animals are based on data from group 1 and group 3 animals before SIV infection.

Figure 2

Figure 2

Loss of multifunctional MML-specific CD4+ T cells after SIV infection in recall-vaccinated animals. Flow cytometric analysis of MML-specific memory and effector (CD28+CD95+ and CD28−CD95+/−) CD4+ T cells 2 weeks after recall MML vaccinations by production of CD40L, IFNγ, IL-2, TNFα, or a combination. (A) Pie charts represent fraction of cells that have 4 (yellow), 3 (cyan), 2 (blue), or 1 (purple) function(s). P value calculated by partial permutation test. (B) Delineation of the 15 possible cytokine combinations is shown for SIV− (green) and SIV+ (black). Dots represent individual RM responses. (C) Student t test results between SIV− and SIV+ cytokine responses corresponding to panel B. Pink shading represents a significant P value less than .05. (D) Total frequency of cytokine producing memory and effector CD4+ T cells for SIV− (green) and SIV+ (black) in response to MML stimulation. P values represent partial permutation test results (A) or Student t test results (C).

Figure 3

Figure 3

MML-specific CD4+ T cells are not preferentially infected with SIV 2 weeks after MML vaccination. CD4+ T cells from SIV-infected RMs were sorted into 4 populations: naive (circles), memory (squares), effector (triangles), and MML-specific (inverted triangles) cells. Quantitative real-time PCR was used to determine the SIV infection frequency of each subset after neo MML vaccination (A) or recall MML vaccination (B). Horizontal bar represents median.

Figure 4

Figure 4

Overall CD4+ T cell functionality is decreased after SIV infection. Flow cytometric analysis of SEB-stimulated memory and effector (CD28+CD95+ and CD28−CD95+/−) CD4+ T cells by production of CD40L, IFNγ, IL-2, TNFα, or a combination. (A) Pie charts represent fraction of cells that have 4 (yellow), 3 (cyan), 2 (blue), or 1 (purple) function(s). P value represents partial permutation test. (B) Delineation of the 15 possible cytokine combinations is shown for SIV− (green) and SIV+ (black). Dots represent individual RM responses. (C) Student t test results between SIV− and SIV+ cytokine responses corresponding to panel B. Pink shading represents a significant P value less than .05. (D) Total frequency of cytokine producing memory and effector CD4+ T cells for SIV− (green) and SIV+ (black) RMs in response to SEB stimulation. P values represent partial permutation test results (A) or Student t test results (C). SEB responses from uninfected animals are based on data from group 1 and group 3 animals before SIV infection.

Figure 5

Figure 5

MML-specific cmASCs are altered after SIV infection. ELISpot analysis of classic memory (CD27+) B-cell Ig responses (cmASCs). (A-B) Specific for MML or (C) total Ig (heavy and light chain, positive control). (A) Number (per 106 cells) of MML-specific cmASCs 2 weeks after neo MML vaccination for IgG (left), IgM (center), or IgA (right). (B) Number (per 106 cells) of MML-specific cmASCs 2 weeks after recall MML vaccination for IgG (left), IgM (center), or IgA (right). (C) Number (per 106 cells) of total Ig cmASCs 2 weeks after neo or recall MML vaccination for IgG (left), IgM (center), or IgA (right). SIV− RMs (circles) and SIV+ RMs (squares). P values represent Mann-Whitney U t test results, horizontal bar represents median. For one animal (CE5D), we did not have sufficient cells to perform the IgA assay.

Figure 6

Figure 6

CD4+ Tfh cells are preferentially SIV-infected in LNs. CD4+ T cells from LNs of SIV-infected RMs were sorted into 3 populations: naive (circles), central memory (squares), and Tfh cells (inverted triangles). Quantitative real-time PCR was used to determine the SIV infection frequency of each subset. P values represent Mann-Whitney U t test results. Horizontal bar represents median.

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