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Dynamics of Lymphocyte Populations during Trypanosoma cruzi Infection: From Thymocyte Depletion to Differential Cell Expansion/Contraction in Peripheral Lymphoid Organs.

Morrot A, Barreto de Albuquerque J, Berbert LR, de Carvalho Pinto CE, de Meis J, Savino W - J Trop Med (2012)

Bottom Line: In the thymus, although the negative selection process of the T-cell repertoire remains operational, there is a massive thymocyte depletion and abnormal release of immature CD4(+)CD8(+) cells to peripheral lymphoid organs, where they acquire an activated phenotype similar to activated effector or memory T cells.Accordingly, T- and B-cell activation is seen in subcutaneous lymph nodes and spleen, but not in mesenteric lymph nodes.Lastly, although the function of peripheral CD4(+)CD8(+) T-cell population remains to be defined in vivo, their presence may contribute to the immunopathological events found in both murine and human Chagas disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, 21045-900 Rio de Janeiro, RJ, Brazil.

ABSTRACT
The comprehension of the immune responses in infectious diseases is crucial for developing novel therapeutic strategies. Here, we review current findings on the dynamics of lymphocyte subpopulations following experimental acute infection by Trypanosoma cruzi, the causative agent of Chagas disease. In the thymus, although the negative selection process of the T-cell repertoire remains operational, there is a massive thymocyte depletion and abnormal release of immature CD4(+)CD8(+) cells to peripheral lymphoid organs, where they acquire an activated phenotype similar to activated effector or memory T cells. These cells apparently bypassed the negative selection process, and some of them are potentially autoimmune. In infected animals, an atrophy of mesenteric lymph nodes is also observed, in contrast with the lymphocyte expansion in spleen and subcutaneous lymph nodes, illustrating a complex and organ specific dynamics of lymphocyte subpopulations. Accordingly, T- and B-cell activation is seen in subcutaneous lymph nodes and spleen, but not in mesenteric lymph nodes. Lastly, although the function of peripheral CD4(+)CD8(+) T-cell population remains to be defined in vivo, their presence may contribute to the immunopathological events found in both murine and human Chagas disease.

No MeSH data available.


Related in: MedlinePlus

Lymphocyte subsets in central and peripheral lymphoid organs from T. cruzi acutely infected mice. Male BALB/c mice were infected intraperitoneally with 10² culture-derived trypomastigotes of T. cruzi (Tulahuén strain), and 14 days after infection the subcutaneous lymph nodes (SCLN), mesenteric lymph nodes (MLN), peritoneal cavity cells (PC), and spleen were harvested to perform flow cytometry. Erythrocytes were previously depleted in the spleen cell suspensions by treatment with Tris-buffered ammonium chloride. The total number of (a) double-negative CD4−CD8− T cells, (b) double-positive CD4+CD8+ T cells, (c) single-positive CD4+ T cells, and (d) CD8+ T cells, (e) CD19+IgDlow B cells and (f) CD19+IgDhigh B cells are indicated for each histogram. Values represent the mean and standard error. The infected group (n = 5–14) were compared to noninfected controls (n = 4–9) with t-test, using the program GraphPad Prism 5. Data were considered significant if P values were <0.05. *P < 0.05, **P < 0.01, ***P < 0.001.
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fig1: Lymphocyte subsets in central and peripheral lymphoid organs from T. cruzi acutely infected mice. Male BALB/c mice were infected intraperitoneally with 10² culture-derived trypomastigotes of T. cruzi (Tulahuén strain), and 14 days after infection the subcutaneous lymph nodes (SCLN), mesenteric lymph nodes (MLN), peritoneal cavity cells (PC), and spleen were harvested to perform flow cytometry. Erythrocytes were previously depleted in the spleen cell suspensions by treatment with Tris-buffered ammonium chloride. The total number of (a) double-negative CD4−CD8− T cells, (b) double-positive CD4+CD8+ T cells, (c) single-positive CD4+ T cells, and (d) CD8+ T cells, (e) CD19+IgDlow B cells and (f) CD19+IgDhigh B cells are indicated for each histogram. Values represent the mean and standard error. The infected group (n = 5–14) were compared to noninfected controls (n = 4–9) with t-test, using the program GraphPad Prism 5. Data were considered significant if P values were <0.05. *P < 0.05, **P < 0.01, ***P < 0.001.

Mentions: The intrinsic balance among the lymphoid organs dictating the functional properties of the lymphocyte subsets are critical for establishing the immune response to T. cruzi infection [9]. Although the intrathymic checkpoints necessary to avoid the maturation of T cells expressing a forbidden T-cell receptor repertoire are present in the acute phase of murine Chagas disease, it has been shown that significant amounts of double-negative and double-positive thymocytes (Figure 1) are abnormally released from infected thymus to the periphery [12, 13, 35]. Considering that among thymus-derived CD4+CD8+ lymphocytes exhibit potentially autoimmune TCRs, we raised the hypothesis that they could be activated in peripheral lymphoid organs. This prompted us to evaluate in acutelyinfected mice whether those cells exhibited an activated profile similar to effector/memory single-positive T cells. The existence of this unconventional and rare (<5%) lymphocyte population in the periphery was explained as a premature release of DP cells from the thymus into the periphery, where their maturation into functionally competent single-positive cells continues [12, 35]. There is, however, considerable evidence of an increased frequency of peripheral CD4+CD8+ T cells during viral infections and during acute T. cruzi infection. For example, in human immunodeficiency virus or Epstein-Barr virus infections, the percentage of DP cells can increase to 20% of all circulating lymphocytes [36, 37]. This fluctuation is also present in the secondary lymph nodes as we demonstrated in the experimental model of Chagas disease, in which DP cell subset increases up to 16 times in subcutaneous lymph nodes [12, 13].


Dynamics of Lymphocyte Populations during Trypanosoma cruzi Infection: From Thymocyte Depletion to Differential Cell Expansion/Contraction in Peripheral Lymphoid Organs.

Morrot A, Barreto de Albuquerque J, Berbert LR, de Carvalho Pinto CE, de Meis J, Savino W - J Trop Med (2012)

Lymphocyte subsets in central and peripheral lymphoid organs from T. cruzi acutely infected mice. Male BALB/c mice were infected intraperitoneally with 10² culture-derived trypomastigotes of T. cruzi (Tulahuén strain), and 14 days after infection the subcutaneous lymph nodes (SCLN), mesenteric lymph nodes (MLN), peritoneal cavity cells (PC), and spleen were harvested to perform flow cytometry. Erythrocytes were previously depleted in the spleen cell suspensions by treatment with Tris-buffered ammonium chloride. The total number of (a) double-negative CD4−CD8− T cells, (b) double-positive CD4+CD8+ T cells, (c) single-positive CD4+ T cells, and (d) CD8+ T cells, (e) CD19+IgDlow B cells and (f) CD19+IgDhigh B cells are indicated for each histogram. Values represent the mean and standard error. The infected group (n = 5–14) were compared to noninfected controls (n = 4–9) with t-test, using the program GraphPad Prism 5. Data were considered significant if P values were <0.05. *P < 0.05, **P < 0.01, ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig1: Lymphocyte subsets in central and peripheral lymphoid organs from T. cruzi acutely infected mice. Male BALB/c mice were infected intraperitoneally with 10² culture-derived trypomastigotes of T. cruzi (Tulahuén strain), and 14 days after infection the subcutaneous lymph nodes (SCLN), mesenteric lymph nodes (MLN), peritoneal cavity cells (PC), and spleen were harvested to perform flow cytometry. Erythrocytes were previously depleted in the spleen cell suspensions by treatment with Tris-buffered ammonium chloride. The total number of (a) double-negative CD4−CD8− T cells, (b) double-positive CD4+CD8+ T cells, (c) single-positive CD4+ T cells, and (d) CD8+ T cells, (e) CD19+IgDlow B cells and (f) CD19+IgDhigh B cells are indicated for each histogram. Values represent the mean and standard error. The infected group (n = 5–14) were compared to noninfected controls (n = 4–9) with t-test, using the program GraphPad Prism 5. Data were considered significant if P values were <0.05. *P < 0.05, **P < 0.01, ***P < 0.001.
Mentions: The intrinsic balance among the lymphoid organs dictating the functional properties of the lymphocyte subsets are critical for establishing the immune response to T. cruzi infection [9]. Although the intrathymic checkpoints necessary to avoid the maturation of T cells expressing a forbidden T-cell receptor repertoire are present in the acute phase of murine Chagas disease, it has been shown that significant amounts of double-negative and double-positive thymocytes (Figure 1) are abnormally released from infected thymus to the periphery [12, 13, 35]. Considering that among thymus-derived CD4+CD8+ lymphocytes exhibit potentially autoimmune TCRs, we raised the hypothesis that they could be activated in peripheral lymphoid organs. This prompted us to evaluate in acutelyinfected mice whether those cells exhibited an activated profile similar to effector/memory single-positive T cells. The existence of this unconventional and rare (<5%) lymphocyte population in the periphery was explained as a premature release of DP cells from the thymus into the periphery, where their maturation into functionally competent single-positive cells continues [12, 35]. There is, however, considerable evidence of an increased frequency of peripheral CD4+CD8+ T cells during viral infections and during acute T. cruzi infection. For example, in human immunodeficiency virus or Epstein-Barr virus infections, the percentage of DP cells can increase to 20% of all circulating lymphocytes [36, 37]. This fluctuation is also present in the secondary lymph nodes as we demonstrated in the experimental model of Chagas disease, in which DP cell subset increases up to 16 times in subcutaneous lymph nodes [12, 13].

Bottom Line: In the thymus, although the negative selection process of the T-cell repertoire remains operational, there is a massive thymocyte depletion and abnormal release of immature CD4(+)CD8(+) cells to peripheral lymphoid organs, where they acquire an activated phenotype similar to activated effector or memory T cells.Accordingly, T- and B-cell activation is seen in subcutaneous lymph nodes and spleen, but not in mesenteric lymph nodes.Lastly, although the function of peripheral CD4(+)CD8(+) T-cell population remains to be defined in vivo, their presence may contribute to the immunopathological events found in both murine and human Chagas disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, 21045-900 Rio de Janeiro, RJ, Brazil.

ABSTRACT
The comprehension of the immune responses in infectious diseases is crucial for developing novel therapeutic strategies. Here, we review current findings on the dynamics of lymphocyte subpopulations following experimental acute infection by Trypanosoma cruzi, the causative agent of Chagas disease. In the thymus, although the negative selection process of the T-cell repertoire remains operational, there is a massive thymocyte depletion and abnormal release of immature CD4(+)CD8(+) cells to peripheral lymphoid organs, where they acquire an activated phenotype similar to activated effector or memory T cells. These cells apparently bypassed the negative selection process, and some of them are potentially autoimmune. In infected animals, an atrophy of mesenteric lymph nodes is also observed, in contrast with the lymphocyte expansion in spleen and subcutaneous lymph nodes, illustrating a complex and organ specific dynamics of lymphocyte subpopulations. Accordingly, T- and B-cell activation is seen in subcutaneous lymph nodes and spleen, but not in mesenteric lymph nodes. Lastly, although the function of peripheral CD4(+)CD8(+) T-cell population remains to be defined in vivo, their presence may contribute to the immunopathological events found in both murine and human Chagas disease.

No MeSH data available.


Related in: MedlinePlus