Research Analyst Indiana Univ. Sch. of Med. Brazil, Indiana, United States
Disclosure(s):
Kamryn Zadeii: No financial relationships to disclose
Introduction/Rationale: The transcription factor T-bet is classically considered as the master-regulator of CD4⁺ T cell-derived IFN-γ, which is essential for host immunity against the intracellular parasite Toxoplasma gondii. Our group and others have previously demonstrated that whole-body T-bet-deficient (Tbx21⁻/⁻) mice rapidly succumb to infection despite retaining CD4⁺ T cell-derived IFN-γ, indicating T-bet has additional roles in mediating host resistance. Recently, our group demonstrated that T-bet-dependent IFN-γ production by group 1 innate lymphoid cells (ILC1s) is critical to maintain type I conventional DCs (cDC1s) that are essential for parasite control and host survival. To further define the role of T-bet in Th1-mediated immunity, we investigated whether T-bet expression in CD4⁺ T cells is required for acute resistance to infection.
Methods: Using a Cre-Lox system to specifically delete Tbx21 in CD4⁺ T cells (CD4-Tbx21⁻/⁻) and adoptive transfers into Rag2⁻/⁻mice, we assessed CD4+ IFN-γ production, parasite burden, cytokine responses, and host survival following systemic or mucosal infection.
Results: We observed CD4-Tbx21⁻/⁻ CD4+ T cells produced less IFN-γ and exhibited partial migration defects. In striking contrast to Tbx21⁻/⁻ mice, CD4-Tbx21⁻/⁻ mice controlled infection and did not succumb rapidly. Moreover, adoptively transferred T-bet-deficient CD4⁺ T cells migrated to lymphoid and intestinal sites and had no defect in IFN-γ production. Furthermore, Tbx21⁻/⁻ dendritic cells preserved functional antigen presentation.
Conclusion: These findings demonstrate that T-bet-independent CD4⁺ T cell effector functions are sufficient for parasite control and host survival during acute T. gondii infection. Understanding how T-bet-independent CD4⁺ T cells mediate acute immunity against T. gondii can provide translational implications for targeting T-bet-independent cell-mediated immunity for not only T. gondii, but other intracellular pathogens such as Listeria, Mycobacteria, and Salmonella.
