A review of CD4+ T cell differentiation and diversity in dogs

Abstract

CD4⁺ T cells are an integral component of the adaptive immune response, carrying out many functions to combat a diverse range of pathogenic challenges. These cells exhibit remarkable plasticity, differentiating into specialized subsets such as T helper type 1 (T_H1), T_H2, T_H9, T_H17, T_H22, regulatory T cells (Tregs), and follicular T helper (T_FH) cells. Each subset is capable of addressing a distinct immunological need ranging from pathogen eradication to regulation of immune homeostasis. As the immune response subsides, CD4⁺ T cells rest down into long-lived memory phenotypes—including central memory (T_CM), effector memory (T_EM), resident memory (T_RM), and terminally differentiated effector memory cells (T_EMRA) that are localized to facilitate a swift and potent response upon antigen re-encounter. This capacity for long-term immunological memory and rapid reactivation upon secondary exposure highlights the role CD4⁺ T cells play in sustaining both adaptive defense mechanisms and maintenance.

Decades of mouse, human, and to a lesser extent, pig T cell research has provided the framework for understanding the role of CD4⁺ T cells in immune responses, but these model systems do not always mimic each other. Although our understanding of pig immunology is not as extensive as mouse or human research, we have gained valuable insight by studying this model. More akin to pigs, our understanding of CD4⁺ T cells in dogs is much less complete. This disparity exists in part because canine immunologists depend on paradigms from mouse and human studies to characterize CD4⁺ T cells in dogs, with a fraction of available lineage-defining antibody markers. Despite this, every major CD4⁺ T cell subset has been described to some extent in dogs. These subsets have been studied in various contexts, including in vitro stimulation, homeostatic conditions, and across a range of disease states. Canine CD4⁺ T cells have been categorized according to lineage-defining characteristics, trafficking patterns, and what cytokines they produce upon stimulation. This review addresses our current understanding of canine CD4⁺ T cells from a comparative perspective by highlighting both the similarities and differences from mouse, human, and pig CD4⁺ T cell biology. We also discuss knowledge gaps in our current understanding of CD4⁺ T cells in dogs that could provide direction for future studies in the field.