Biology subjects

Klonowski, K. D.

Publications and source records attributed to Klonowski, K. D..

3 recordsLinked to original sources

bioRxiv2025

Adult mice with neonatal-like T cell subsets exhibit increased susceptibility to Bordetella pertussis and influenza infection

Infants are significantly more susceptible to respiratory infection, often resulting in increased morbidity and hospitalization, and occasionally death. This susceptibility is partially explained by the developing nature of the thymus in human infants at, and for several months after, birth. However, the contribution of T cells produced in this thymic microenvironment to infant immune responses has received minimal investigation. Here, we utilized a previously described mouse model (Foxn1{Delta}/{Delta}) which exhibits a persistently immature thymus. Through further characterization, we have determined that adult Foxn1{Delta}/{Delta} mice retain some unique T cells observed in neonatal mice including CD8{beta}+ {gamma}{delta} T cells and CD8 T cells displaying a memory-like phenotype. For this reason, we assessed the potential of these neonatal-like T responses to two pathogens which disproportionately affect neonates, Bordetella pertussis (Bp) and influenza. Utilizing these infections, we demonstrate that T cells generated in an incompletely developed thymus fail to control or mount an effective response against Bp. We also observe that Foxn1{Delta}/{Delta} mice control acute influenza infection, a response which does not require IL-17. However, the Foxn1{Delta}/{Delta} mice fail to generate an influenza nucleoprotein (NP) specific CD8+ T cell response which is likely associated with their inability to fully clear the infection. Together, these data suggest that Foxn1{Delta}/{Delta} mice can be utilized to study the generation, function, and persistence of some unique T cells made in a neonatal-like thymus.

immunology↗

bioRxiv2025

Memory Regulatory T Cells Reprogram into Protective Tfh-like Effectors in Recurrent Malaria

Although people living in malaria-endemic areas experience repeated infections with Plasmodium, the role of regulatory T cells (Tregs) in recurrent malaria remains poorly understood. During a primary infection with Plasmodium, Tregs suppress protective immunity by inhibiting germinal center (GC) reactions, thereby impeding the control of parasitemia. In contrast, we demonstrate here that memory Tregs (mTregs) remaining after the clearance of initial Plasmodium infection acquire protective functions upon recall. Relying on longitudinal studies in humans and mice, we show that mTregs undergo antigen-driven expansion and inflammation-induced epigenetic reprogramming during reinfection to transition from Foxp3+ immunosuppressive cells to Bcl6+ follicular T helper (Tfh)-like effectors. These mTreg-derived Tfh-like cells enhance GC responses and the generation of Plasmodium-specific antibodies, ultimately facilitating Plasmodium control. Precluding such mTreg-to-Tfh differentiation abolished protection. Our findings reveal a previously unrecognized adaptive plasticity in canonical mTregs that enables a context-dependent functional switch from immunoregulatory to protective effectors during recurrent infections.

immunology↗

bioRxiv2024

Premature thymic involution in young Foxn1lacz mutant mice causes peripheral T cell phenotypes similar to aging-induced immunosenescence

The thymus is a primary lymphoid organ generating self-restricted and self-tolerant naive T-cells. Early in life the thymus starts to involute, resulting in decreased naive T-cell output which may be more self-reactive, leading to an increased prevalence of autoimmunity. A decrease in the transcription factor FOXN1 is an early event in thymic involution. Using the Foxn1lacz model, we studied how premature thymic involution affects the thymic microenvironment, thymocytes, and peripheral T cell immunity. We found that early thymic involution led to aged-like thymic epithelial cells that resulted in aged-like thymocyte phenotypes, with a significant decrease in CD4+ single-positive T-cells. We also observed severe lymphopenia in Foxn1lacz mice caused by the premature decrease in T-cell production, resulting in a peripheral T-cell phenotype similar to de novo aged peripheral T-cells. Moreover, following T cell receptor stimulation, Foxn1lacz peripheral T cells had reduced IL-2 secretion and strong initial IFN-g responses, resembling aged wild-type peripheral T-cell responses. Lastly, influenza response in Foxn1lacz had a reduction in some aspects of T cell responses to influenza infection, similar to thymectomized mice. Our study shows an independent and direct impact of premature thymic involution on both thymopoiesis and peripheral immune niches likely contributing to immunosenescence and inflammaging as observed in the elderly population.

immunology↗