Variants in human CD48 lead to impaired T cell immunity and increased inflammation
Samantha Milanesi, Tiziana Lorenzini, Tommaso Marchetti, Diana Tintor, Raquel Planas, Ola Sabet, Lars Malmström, Sudip Acharya, Carson D. Williams, Zoe E. Manning, Jack H. Roser, Angelica C. Ehler, Michael Huber, Seraina Prader, Stefano Vavassori, Cullen M. Dutmer, Jordan K. Abbott, Jana Pachlopnik Schmid
Samantha Milanesi, Tiziana Lorenzini, Tommaso Marchetti, Diana Tintor, Raquel Planas, Ola Sabet, Lars Malmström, Sudip Acharya, Carson D. Williams, Zoe E. Manning, Jack H. Roser, Angelica C. Ehler, Michael Huber, Seraina Prader, Stefano Vavassori, Cullen M. Dutmer, Jordan K. Abbott, Jana Pachlopnik Schmid
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Research Article Immunology Inflammation

Variants in human CD48 lead to impaired T cell immunity and increased inflammation

Abstract

CD48 is a surface molecule with immunoregulatory functions. Following our initial report of a patient with a de novo heterozygous variant at amino acid S220 in the CD48 gene, we describe a second, unrelated patient with similar features of immune dysregulation and a missense change affecting the same residue. To further elucidate the specific pathogenic mechanisms of the identified variants, we reviewed patient records, analyzed patient-derived cells, and employed complementary in vitro and in vivo model systems, including transfected cell lines and CD48-deficient mice. We demonstrate that the variants are associated with altered distribution of CD48, characterized by diminished CD48 surface expression, intracellular retention, and activation of ER stress signaling. Patient T cells displayed increased susceptibility to apoptosis, reduced antiviral responses, and enhanced inflammation. Both patients exhibited T cell lymphopenia, a restricted T cell receptor repertoire diversity, and oligoclonal expansions consistent with antigen-driven selection. In parallel, virally infected CD48-deficient mice recapitulate key aspects of the human phenotype, including delayed antiviral immune responses, impaired viral clearance, and pronounced inflammation. We conclude that identified variants compromise CD48 cell surface localization, impair T cell survival and function, and predispose to inflammation, thereby highlighting the role of CD48 in immune regulation and the prevention of excessive inflammation.

Authors

Samantha Milanesi, Tiziana Lorenzini, Tommaso Marchetti, Diana Tintor, Raquel Planas, Ola Sabet, Lars Malmström, Sudip Acharya, Carson D. Williams, Zoe E. Manning, Jack H. Roser, Angelica C. Ehler, Michael Huber, Seraina Prader, Stefano Vavassori, Cullen M. Dutmer, Jordan K. Abbott, Jana Pachlopnik Schmid

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Figure 1

Genetic and immunologic characteristics of patients with different CD48 S220 variants.

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Genetic and immunologic characteristics of patients with different CD48 ...
(A) Family trees showing male (square) and female (circle) family members; open symbols represent HDs, and solid symbols represent the patients (P1 and P2). Below, Sanger sequencing of the CD48 gene (exon 4), showing the identified variants in both patients. (B) The CD48 protein structure predicted using AlphaFold 2 (47) and colored by per-residue confidence (predicted local distance difference test). Blue, very high; light blue, high; yellow, low; orange, very low. The identified ω-site amino acid substitutions were modeled using PDB 8IMY, and the PIGK–UL16-Binding Protein 2 complex was visualized using ChimeraX (48). Conservation, ΔΔG stability change, and CADD scores were obtained using ProtVar (49). Conservation 0.45–0.60, moderate; ΔΔG < 2 kcal/mol, unlikely destabilizing; CADD 20–24.9, likely deleterious. (C) Change over time in the leukocyte (blue), lymphocyte (red), CD4+ T cell (red), and CD8+ T cell (blue) blood counts measured in giga per liter (G/L) in P1 (light red and light blue) and P2 (dark red and dark blue). Red bars indicate inflammatory episodes; dotted lines indicate reference intervals. (D) Truncated violin plots showing the median and quartiles of the frequencies of EM, terminally differentiated effector memory (TEMRA), and CD31+CD38+ naive CD4+ T cells, and naive, non-naive, and CD31+CD38+ naive CD8+ T cells in 15 adult HDs (blue dots) compared with P1 (orange and red dots) and P2 (dark red dots). The ages at measurement for P1 and P2 are indicated. Due to the low patient sample size, no statistical analysis was performed. (E) Overlaid flow cytometry histograms of CD48 surface expression, reported as geometric MFI (gMFI), in peripheral blood cell subsets in 2 adult HDs (blue), P1 (red), and P2 (dark red). (F) CADD–minor allele frequency (MAF) graph of CD48 variants reported in gnomAD. Heterozygous (HET) variants, light blue; HET loss of function (LOF), red; homozygous (HOM) isomorphic, green.