GPA33 is expressed on multiple human blood cell types and distinguishes CD4<sup>+</sup> central memory T cells with and without effector function

Opstelten, Rianne; Suwandi, Jessica S.; Slot, Manon C.; Morgana, Florencia; Scott, Andrew; Laban, Sandra; Nikolić, Tatjana; Turksma, Annelies W.; Kroeze, Anna; Voermans, Carlijn; Zwaginga, Jaap‐Jan; Roep, Bart O.; Amsen, Derk

doi:10.1002/eji.202048744

Cited by 5 publications

(3 citation statements)

References 41 publications

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“…The magnitude of DC binding by ATR-107 was not meaningfully different than a control antibody with low immunogenic potential (PF-1) 50 . As for HuA33, other factors besides the therapeutic target (glycoprotein A33) are expected to contribute to its high immunogenic potential since GPA33 has little expression on human DCs and monocytes 60 .…”

Section: Discussionmentioning

confidence: 99%

A mechanistic marker-based screening tool to predict clinical immunogenicity of biologics

Jarvi,

Balu-Iyer

2023

Commun Med

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Background The efficacy and safety of therapeutic proteins are undermined by immunogenicity driven by anti-drug antibodies. Immunogenicity risk assessment is critically necessary during drug development, but current methods lack predictive power and mechanistic insight into antigen uptake and processing leading to immune response. A key mechanistic step in T-cell-dependent immune responses is the migration of mature dendritic cells to T-cell areas of lymphoid compartments, and this phenomenon is most pronounced in the immune response toward subcutaneously delivered proteins. Methods The migratory potential of monocyte-derived dendritic cells is proposed to be a mechanistic marker for immunogenicity screening. Following exposure to therapeutic protein in vitro, dendritic cells are analyzed for changes in activation markers (CD40 and IL-12) in combination with levels of the chemokine receptor CXCR4 to represent migratory potential. Then a transwell assay captures the intensity of dendritic cell migration in the presence of a gradient of therapeutic protein and chemokine ligands. Results Here, we show that an increased ability of the therapeutic protein to induce dendritic cell migration along a gradient of chemokine CCL21 and CXCL12 predicts higher immunogenic potential. Expression of the chemokine receptor CXCR4 on human monocyte-derived dendritic cells, in combination with activation markers CD40 and IL-12, strongly correlates with clinical anti-drug antibody incidence. Conclusions Mechanistic understanding of processes driving immunogenicity led to the development of a predictive tool for immunogenicity risk assessment of therapeutic proteins. These predictive markers could be adapted for immunogenicity screening of other biological modalities.

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Section: Discussionmentioning

confidence: 99%

A mechanistic marker-based screening tool to predict clinical immunogenicity of biologics

Jarvi,

Balu-Iyer

2023

Commun Med

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“…A cell surface antigen. Associated with immune dysregulation [ 62 ]. High expression of GPA33 defines CD4 + CD25 + CD127 – FoxP3 + Helios + Tregs that are unable to produce conventional T (Tconv) cells effector cytokines.…”

Section: Markers Suitable For Determination Of Tregsmentioning

confidence: 99%

Many Faces of Regulatory T Cells: Heterogeneity or Plasticity?

Blinova,

Zhdanov

2024

Cells

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Regulatory T cells (Tregs) are essential for maintaining the immune balance in normal and pathological conditions. In autoimmune diseases and transplantation, they restrain the loss of self-tolerance and promote engraftment, whereas in cancer, an increase in Treg numbers is mostly associated with tumor growth and poor prognosis. Numerous markers and their combinations have been used to identify Treg subsets, demonstrating the phenotypic diversity of Tregs. The complexity of Treg identification can be hampered by the unstable expression of some markers, the decrease in the expression of a specific marker over time or the emergence of a new marker. It remains unclear whether such phenotypic shifts are due to new conditions or whether the observed changes are due to initially different populations. In the first case, cellular plasticity is observed, whereas in the second, cellular heterogeneity is observed. The difference between these terms in relation to Tregs is rather blurred. Considering the promising perspectives of Tregs in regenerative cell-based therapy, the existing confusing data on Treg phenotypes require further investigation and analysis. In our review, we introduce criteria that allow us to distinguish between the heterogeneity and plasticity of Tregs normally and pathologically, taking a closer look at their diversity and drawing the line between two terms.

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“…The continuous splitting of Treg populations into subsets on the basis of new candidate markers adds to the confusion when classifying Treg sub-entities, which can share phenotypic and functional features irrespective of their origin that sometimes overlap with activated Teff cells ( Figure 1 ). Furthermore, supposed Treg markers such as GITR, Lag-3, and glycoprotein A33 (GPA33) and others ( Table 1 ) can be expressed by activated Teff cells to regulate/modulate T cell activation and may be linked to the contraction of T cells after activation to regain immune homeostasis [ 57 , 58 , 59 , 60 , 61 ]. For example, Lag-3 is upregulated on all T cells upon TCR activation or by certain cytokines [ 57 ].…”

Section: Revisiting Human Treg Phenotypesmentioning

confidence: 99%

Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function

Gootjes,

Zwaginga,

Roep

et al. 2024

Cells

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Regulatory T cells (Tregs) are essential to maintain immune homeostasis by promoting self-tolerance. Reduced Treg numbers or functionality can lead to a loss of tolerance, increasing the risk of developing autoimmune diseases. An overwhelming variety of human Tregs has been described, based on either specific phenotype, tissue compartment, or pathological condition, yet the bulk of the literature only addresses CD25-positive and CD127-negative cells, coined by naturally occurring Tregs (nTregs), most of which express the transcription factor Forkhead box protein 3 (FOXP3). While the discovery of FOXP3 was seminal to understanding the origin and biology of nTregs, there is evidence in humans that not all T cells expressing FOXP3 are regulatory, and that not all Tregs express FOXP3. Namely, the activation of human T cells induces the transient expression of FOXP3, irrespective of whether they are regulatory or inflammatory effectors, while some induced T cells that may be broadly defined as Tregs (e.g., Tr1 cells) typically lack demethylation and do not express FOXP3. Furthermore, it is unknown whether and how many nTregs exist without FOXP3 expression. Several other candidate regulatory molecules, such as GITR, Lag-3, GARP, GPA33, Helios, and Neuropilin, have been identified but subsequently discarded as Treg-specific markers. Multiparametric analyses have uncovered a plethora of Treg phenotypes, and neither single markers nor combinations thereof can define all and only Tregs. To date, only the functional capacity to inhibit immune responses defines a Treg and distinguishes Tregs from inflammatory T cells (Teffs) in humans. This review revisits current knowledge of the Treg universe with respect to their heterogeneity in phenotype and function. We propose that it is unavoidable to characterize human Tregs by their phenotype in combination with their function, since phenotype alone does not unambiguously define Tregs. There is an unmet need to align the expression of specific markers or combinations thereof with a particular suppressive function to coin functional Treg entities and categorize Treg diversity.

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GPA33 is expressed on multiple human blood cell types and distinguishes CD4⁺ central memory T cells with and without effector function

Cited by 5 publications

References 41 publications

A mechanistic marker-based screening tool to predict clinical immunogenicity of biologics

A mechanistic marker-based screening tool to predict clinical immunogenicity of biologics

Many Faces of Regulatory T Cells: Heterogeneity or Plasticity?

Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function

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GPA33 is expressed on multiple human blood cell types and distinguishes CD4+ central memory T cells with and without effector function

Cited by 5 publications

References 41 publications

A mechanistic marker-based screening tool to predict clinical immunogenicity of biologics

A mechanistic marker-based screening tool to predict clinical immunogenicity of biologics

Many Faces of Regulatory T Cells: Heterogeneity or Plasticity?

Defining Human Regulatory T Cells beyond FOXP3: The Need to Combine Phenotype with Function

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GPA33 is expressed on multiple human blood cell types and distinguishes CD4⁺ central memory T cells with and without effector function