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Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott-Aldrich Syndrome.

Cotta-de-Almeida V, Dupré L, Guipouy D, Vasconcelos Z - Front Immunol (2015)

Bottom Line: Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches.Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system.These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions.

View Article: PubMed Central - PubMed

Affiliation: Oswaldo Cruz Institute, Fiocruz , Rio de Janeiro , Brazil.

ABSTRACT
Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches. Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system. In this review, we highlight the research that has focused over the last 20 years on T lymphocytes from Wiskott-Aldrich syndrome (WAS) patients. WAS T lymphocytes are defective for the WAS protein (WASP), a regulator of actin cytoskeleton remodeling. Therefore, study of WAS T lymphocytes has helped to grasp that many steps of T lymphocyte activation and function depend on the crosstalk between membrane receptors and the actin cytoskeleton. These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions. The recent concept that WASP also works as a regulator of transcription within the nucleus is an illustration of the complexity of signal integration in T lymphocytes. Finally, this review will discuss how further study of WAS may contribute to solve novel challenges of T lymphocyte biology.

No MeSH data available.


Related in: MedlinePlus

Defects of T cell subsets and link to clinical manifestations. As WASP is required for many functions, its absence results in defects of cellular function. We have listed those impairments for human T cell subsets that have been described in the literature. Black arrows show the function exerted by each T cell types, with dotted arrows to point out unknown WASP implication. Red crosses point out the most prominent impairments described in WAS T cells. APC, antigen-presenting cell; pMHC, peptide/major histocompatibility complex; TCR, T-cell receptor, TGF-β, transforming growth factor β.
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Figure 3: Defects of T cell subsets and link to clinical manifestations. As WASP is required for many functions, its absence results in defects of cellular function. We have listed those impairments for human T cell subsets that have been described in the literature. Black arrows show the function exerted by each T cell types, with dotted arrows to point out unknown WASP implication. Red crosses point out the most prominent impairments described in WAS T cells. APC, antigen-presenting cell; pMHC, peptide/major histocompatibility complex; TCR, T-cell receptor, TGF-β, transforming growth factor β.

Mentions: Wiskott–Aldrich syndrome protein plays multiple roles in effector CD4+ T cells since it regulates motility, immunological synapse stability, signal integration, and cytokine production (Figure 3). T lymphocytes from WAS patients were originally found to display reduced chemotaxis in response to the T-cell chemoattractant stromal cell-derived factor (SDF)-1 (73). On the other hand, WASP-deficient CD4+ T cells display increased T cell motility upon encounter with non-cognate dendritic cells or B cells and reduced capacity to stop following antigen recognition (58). As an integrator of multiple signals arising from chemokine receptors, integrins, and the TCR, WASP may therefore modulate differently the motility of T cells depending on the context. As expected from the in vitro findings, WASP-deficient CD4+ T cells from the Was−/− murine model display abnormal trafficking and scanning abilities. Indeed, the homing of WASP-deficient lymphocytes to Peyer’s patches is significantly impaired upon adoptive transfer into recipient mice, when compared to wild-type lymphocytes (48). Although not formally demonstrated, it is highly probable that CD4+ T cell motility defects contribute to the immunocompromised status of WAS patients.


Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott-Aldrich Syndrome.

Cotta-de-Almeida V, Dupré L, Guipouy D, Vasconcelos Z - Front Immunol (2015)

Defects of T cell subsets and link to clinical manifestations. As WASP is required for many functions, its absence results in defects of cellular function. We have listed those impairments for human T cell subsets that have been described in the literature. Black arrows show the function exerted by each T cell types, with dotted arrows to point out unknown WASP implication. Red crosses point out the most prominent impairments described in WAS T cells. APC, antigen-presenting cell; pMHC, peptide/major histocompatibility complex; TCR, T-cell receptor, TGF-β, transforming growth factor β.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4321635&req=5

Figure 3: Defects of T cell subsets and link to clinical manifestations. As WASP is required for many functions, its absence results in defects of cellular function. We have listed those impairments for human T cell subsets that have been described in the literature. Black arrows show the function exerted by each T cell types, with dotted arrows to point out unknown WASP implication. Red crosses point out the most prominent impairments described in WAS T cells. APC, antigen-presenting cell; pMHC, peptide/major histocompatibility complex; TCR, T-cell receptor, TGF-β, transforming growth factor β.
Mentions: Wiskott–Aldrich syndrome protein plays multiple roles in effector CD4+ T cells since it regulates motility, immunological synapse stability, signal integration, and cytokine production (Figure 3). T lymphocytes from WAS patients were originally found to display reduced chemotaxis in response to the T-cell chemoattractant stromal cell-derived factor (SDF)-1 (73). On the other hand, WASP-deficient CD4+ T cells display increased T cell motility upon encounter with non-cognate dendritic cells or B cells and reduced capacity to stop following antigen recognition (58). As an integrator of multiple signals arising from chemokine receptors, integrins, and the TCR, WASP may therefore modulate differently the motility of T cells depending on the context. As expected from the in vitro findings, WASP-deficient CD4+ T cells from the Was−/− murine model display abnormal trafficking and scanning abilities. Indeed, the homing of WASP-deficient lymphocytes to Peyer’s patches is significantly impaired upon adoptive transfer into recipient mice, when compared to wild-type lymphocytes (48). Although not formally demonstrated, it is highly probable that CD4+ T cell motility defects contribute to the immunocompromised status of WAS patients.

Bottom Line: Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches.Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system.These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions.

View Article: PubMed Central - PubMed

Affiliation: Oswaldo Cruz Institute, Fiocruz , Rio de Janeiro , Brazil.

ABSTRACT
Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches. Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system. In this review, we highlight the research that has focused over the last 20 years on T lymphocytes from Wiskott-Aldrich syndrome (WAS) patients. WAS T lymphocytes are defective for the WAS protein (WASP), a regulator of actin cytoskeleton remodeling. Therefore, study of WAS T lymphocytes has helped to grasp that many steps of T lymphocyte activation and function depend on the crosstalk between membrane receptors and the actin cytoskeleton. These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions. The recent concept that WASP also works as a regulator of transcription within the nucleus is an illustration of the complexity of signal integration in T lymphocytes. Finally, this review will discuss how further study of WAS may contribute to solve novel challenges of T lymphocyte biology.

No MeSH data available.


Related in: MedlinePlus