Immune dysregulation and T-cell Exhaustion in people with Down syndrome Restricted; Files Only

Abstract

Down syndrome (DS) affects about 1 in 1000 live births, influencing both development and the

immune system of affected individuals. People with DS face a higher risk and experience poorer

outcomes to respiratory infections, cancer, autoimmune conditions, and cardiovascular

conditions. DS condition arises by full or partial trisomy of chromosome 21, which encodes 4 out

of 6 IFN receptors. The overstimulation of the JAK/STAT pathway leads to chronic inflammation

even in the absence of infection. Consequently, there is chronic stimulation of T cells which leads

to T cell exhaustion. Understanding the role of T cell exhaustion in people with Down syndrome

is crucial to unravelling the comorbidities associated with DS. The phenotypic markers and

transcription factors associated with T cell differentiation were investigated in a cohort

comprising DS (n=59) and non-DS (n=60) from São Paulo, Brazil. Notably, UMAP and Trajectory

Analysis revealed that DS group had statistically significant differences in CD4 and CD8 (non-

parametric Wilcoxon test, p<0.05) expression of clusters of increased differentiation. DS

individuals displayed a more exhausted T cell subset such as TEMRA (terminally differentiated), T

Effector Memory and T transition memory subsets. The phenotype of individuals with DS included

exhaustive intermediate and exhaustive terminal subsets showing a reduction in effector function

based on Granzyme B and TBET expression. In comparison, non-DS individuals express a less

differentiated and more homeostatic T cell repertoire, marked by expression of naïve, central

memory and stem-like subsets. These findings suggest that DS has distinct T cell subsets that

show patterns of exhaustion. Such findings are pivotal for comprehending the immune

dysfunction in individuals with DS, potentially paving the way for developing innovative

therapeutic approaches to reverse exhaustion (JAK/ STAT inhibitors, anti-PD1, anti-SLAMF6).

Table of Contents

Introduction ........................................................................................................................1

Down Syndrome ...................................................................................................................2

DS Demographics .................................................................................................................2

Clinical Manifestation ..........................................................................................................3

Immune System Overview ....................................................................................................4

Interferons and the JAK/STAT Pathway ..................................................................................4

T-lymphocyte cells .............................................................................................................. 6

T cell exhaustion .................................................................................................................8

Markers Defining T cell exhaustion .......................................................................................8

Immune Dysregulation in Down syndrome ...........................................................................11

T cell exhaustion in Down syndrome ...................................................................................13

Methods ............................................................................................................................14

Cohort ..............................................................................................................................14

Sample Collection ..............................................................................................................14

Thawing of PBMC samples ..................................................................................................15

Immunofluorescent Cell Staining ........................................................................................15

Uniform Manifold Approximation and Projection (UMAP) for Dimension Reduction ............... 17

Trajectory Analysis ............................................................................................................18

Statistics ...........................................................................................................................18

Code Availability ................................................................................................................18

Results...............................................................................................................................19

Demographics ....................................................................................................................19

Principal Variance Component Analysis (PVCA) ................................................................... 20

Defining T cell subsets ....................................................................................................... 20

CD8+ T cells ...................................................................................................................... 23

UMAP Analysis and cluster annotations ...............................................................................23

Trajectory Analysis ............................................................................................................ 26

CD4+ T cells ...................................................................................................................... 28

UMAP Analysis and cluster annotations .............................................................................. 28

Trajectory Analysis ............................................................................................................ 31

Discussion......................................................................................................................... 33

Conclusion ........................................................................................................................ 35

Future Directions............................................................................................................... 35

Limitations ........................................................................................................................36

Supplemental Information ..................................................................................................37

References .........................................................................................................................40

About this Honors Thesis

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Emory College
Department	Human Health
Degree	B.A.
Submission	Honors Thesis
Language	English
Research Field	Health Sciences, Immunology Biology, General Health Sciences, Pathology
Palabra Clave	Down Syndrome Immune dysregulation T cell Exhaustion
Committee Chair / Thesis Advisor	Ribeiro, Susan, Emory University
Committee Members	Morran, Levi, Emory University Gavegnano, Christina, Emory University

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