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INTRAEPITHELIAL LYMPHOCYTES: HISTOLOGICAL FEATURES AND
FUNCTIONAL SIGNIFICANCE
Kholdarova Erkinoy Samadullayevna
Andijan State Medical Institute, Uzbekistan
Abstract:
Intraepithelial lymphocytes (IELs) represent a unique population of immune cells
embedded within the epithelial layer of the gastrointestinal tract. Their histological
distribution, morphological features, and immunological roles are essential for maintaining
mucosal homeostasis and providing first-line defense against pathogens. This article aims to
explore the structural characteristics, histological localization, and functional implications of
IELs, integrating current knowledge from experimental and clinical studies.
Keywords:
intraepithelial lymphocytes, histology, gastrointestinal mucosa, CD8+ T cells,
γδ T cells, mucosal immunity, celiac disease
Introduction
Histology provides the fundamental understanding of tissue organization and cellular
architecture, which is indispensable for interpreting pathological alterations. Among
specialized immune cell populations, intraepithelial lymphocytes occupy a crucial position
in the epithelial lining of the gastrointestinal mucosa. Unlike lamina propria lymphocytes,
IELs are interspersed between epithelial cells, allowing them direct interaction with the
external environment and antigens. Their strategic localization highlights their pivotal role in
both immune surveillance and regulation of epithelial integrity. Investigating their
histological features is particularly relevant for comprehending disorders such as celiac
disease, inflammatory bowel disease, and gastrointestinal infections, where IEL numbers
and functions are altered.
The study of IELs is of particular relevance in modern histology because these cells serve as
a bridge between innate and adaptive immunity. They not only exert cytotoxic functions
against infected or transformed epithelial cells but also contribute to epithelial renewal and
barrier maintenance. IELs produce regulatory cytokines, such as interleukin-10 and
transforming growth factor-β, which modulate local inflammation and promote tolerance to
commensal microbiota. At the same time, their ability to secrete interferon-γ and tumor
necrosis factor-α provides robust defense mechanisms against pathogenic challenges.
Histological evaluation of IELs has significant clinical importance. In normal physiology,
IEL counts are tightly regulated and reflect mucosal homeostasis. In various pathological
states, however, their density and phenotypic composition undergo marked alterations. For
instance, an increased number of IELs is one of the earliest and most sensitive
histopathological markers of celiac disease. Similarly, abnormalities in IEL distribution have
been implicated in inflammatory bowel diseases, infectious enteritis, and certain
lymphoproliferative disorders.
Recent advances in immunohistochemistry and molecular profiling have allowed for better
characterization of IEL subsets, particularly the distinction between CD8αα and CD8αβ T
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cells, as well as αβ and γδ T-cell receptor-bearing lymphocytes. These discoveries have
deepened our understanding of how IELs maintain the delicate balance between immune
tolerance and immune activation in the gut. Therefore, histological investigation of IELs is
not only of academic interest but also of substantial diagnostic and therapeutic value.
The present article aims to provide an in-depth analysis of the histological features of
intraepithelial lymphocytes, focusing on their localization, morphology, and immunological
functions, while also discussing their alterations in pathological conditions. By synthesizing
current histological and immunological data, this work underscores the essential role of IELs
in both health and disease, thereby emphasizing their relevance for clinical histopathology.
Methods
The review was based on an integrative analysis of histological, immunohistochemical, and
ultrastructural studies. Histological sections of intestinal biopsies were examined with
hematoxylin and eosin staining to identify IEL distribution. Immunohistochemistry was used
to differentiate T-cell subsets, particularly CD3+, CD8+, and γδ T-cell populations, while
electron microscopy studies provided insight into morphological adaptations. Literature
databases including PubMed, Scopus, and Web of Science were systematically searched for
peer-reviewed articles from 2000 to 2024 focusing on IEL histology and function. Selection
criteria included experimental animal models, human clinical studies, and in vitro
investigations assessing epithelial–lymphocyte interactions.
Histological Analysis:
For the evaluation of IELs, standard hematoxylin and eosin (H&E) staining was used on
paraffin-embedded sections of intestinal biopsies. This technique allowed visualization of
IEL distribution within the epithelial lining and quantification of IEL density per 100
epithelial cells. Morphological features such as nuclear-to-cytoplasmic ratio, chromatin
structure, and cytoplasmic granularity were assessed under light microscopy at
magnifications ranging from ×200 to ×1000.
Immunohistochemistry (IHC):
Immunohistochemical staining was employed to identify lymphocyte subsets and their
phenotypic markers. Monoclonal antibodies against CD3, CD8, CD4, and γδ T-cell receptor
(TCR) were applied to formalin-fixed sections. Staining was visualized with a
diaminobenzidine (DAB) chromogen and counterstained with hematoxylin. The presence
and proportion of IEL subsets were evaluated semi-quantitatively by counting positively
stained cells per high-power field.
Electron Microscopy:
Transmission electron microscopy (TEM) was used in selected studies to characterize the
ultrastructural features of IELs. Small mucosal samples were fixed in glutaraldehyde, post-
fixed in osmium tetroxide, dehydrated in ethanol, and embedded in resin. Ultrathin sections
were stained with uranyl acetate and lead citrate before examination. TEM allowed detailed
assessment of IEL–epithelial junctions, cytoplasmic organelles, and granule content.
Quantitative and Statistical Analysis:
IEL density was reported as the number of IELs per 100 epithelial cells, following
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established histological guidelines. Statistical comparisons between healthy controls and
disease groups (e.g., celiac disease, inflammatory bowel disease) were obtained from pooled
literature data. Where applicable, mean values, standard deviations, and ranges were
reported. Data were synthesized qualitatively to highlight consistent histological patterns
across studies.
Results
Histological analysis consistently demonstrates that IELs are located between columnar
epithelial cells, with the highest density in the small intestine, particularly the jejunum.
Quantitative studies reveal that IELs typically number between 20–40 cells per 100
epithelial cells in healthy individuals. Morphologically, IELs are small-to-medium
lymphocytes with condensed chromatin, scant cytoplasm, and prominent nuclear-to-
cytoplasmic ratio. Immunohistochemical staining highlights the predominance of CD8+ T
cells, with a substantial fraction expressing the γδ T-cell receptor. Electron microscopy
shows close junctional associations between IELs and epithelial cells, suggesting a direct
regulatory role in barrier function. Functionally, IELs secrete cytokines such as interferon-γ
and tumor necrosis factor-α, contributing to mucosal immunity. In pathological conditions
such as celiac disease, IEL counts may exceed 40 per 100 epithelial cells, representing a key
diagnostic marker.
Discussion
The histological features of IELs underline their dual function as both guardians of epithelial
integrity and effectors of adaptive immunity. Their interepithelial positioning facilitates
rapid antigen recognition without the need for migration through tissue layers. The
predominance of cytotoxic CD8+ cells indicates their readiness to eliminate infected or
transformed epithelial cells. Moreover, the presence of γδ T cells reflects an evolutionary
adaptation to provide innate-like immune responses. Alterations in IEL distribution and
phenotype have significant clinical relevance. For example, in celiac disease, an increase in
IELs coupled with villous atrophy serves as a critical histopathological hallmark.
Conversely, IEL depletion may predispose individuals to chronic infections and epithelial
dysregulation. Thus, histological assessment of IELs is an indispensable component of
gastrointestinal pathology.
Conclusion
Intraepithelial lymphocytes represent a distinctive histological and functional unit of the
intestinal mucosa. Their structural localization, morphological attributes, and immunological
roles highlight their importance in maintaining epithelial defense. Understanding their
histological characteristics provides valuable insights into gastrointestinal pathology,
guiding both diagnostic and therapeutic approaches. Future studies integrating advanced
imaging and molecular profiling will further unravel the complexity of IEL–epithelial
interactions, offering new perspectives in mucosal immunology and histopathology.
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