CD4: a vital player in the teleost fish immune system

Abstract

CD4 is a nonpolymorphic transmembrane glycoprotein molecule that is expressed on the surface of T-helper cells and plays an essential role in the immune response. It functions as a coreceptor with the T-cell receptor by binding to major histocompatibility complex class II on the surface of dendritic cells that present antigens. CD4⁺ T cells hold a key position in coordinating the immune system through production of several cytokines after activation and differentiation. The CD4⁺ T helper subtypes (T-helper 1, T-helper 2, T-helper 17, T-helper 9, and regulatory-T cells) perform different immune functions subsequent to their differentiation from the naive T cells. Different types of CD4⁺ T cells require different cytokines such as drivers and effectors, as well as master transcription factors for their activation. Fish cells that express CD4-related genes are activated in the presence of a pathogen and release cytokines against the pathogen. This review highlights the types of CD4⁺ T cells in fish and describes their direct role in cell-mediated and humoral immunity for protection against the intracellular bacterial as well as viral infections in fish.

Figure 1

CD4 cells orchestrating immune response. Recruitment of CD8, B lymphocytes and Macrophages by CD4 cells and production of different interleukins and interferon’s to carry out desired protection against various organisms, equally important for specific and non-specific immunity. Assembly of inflammatory cytokines in fish with infection is triggered, subject to leukocyte mobilization. Activated T-helper cells with CD4 co-receptor, produces IL-2 and IFN-γ to encourage macrophage activation for a general non-specific immune response. Likewise, IL-2 and IL-4 elicit response of B lymphocytes for specific immunity.

Figure 2

Summary of expected CD4+ cell differentiation in fish. Expected Milieu of cytokines (denoted by colored symbols) influencing CD4+ T cell differentiation with (IL-12) causing naïve CD4 cells ultimately differentiated into Th-1 cells to get rid of invading intracellular pathogen i.e. Bacteria, Viruses. Similarly, IL-2, IL-2L, IL-13A, IL-13B brings forth differentiation of Th2 cells in response to extracellular parasitic infectious agent. Differentiated Th-17 cells; autoimmunity and I-Treg cells; homeostasis are produced in response to cytokines IL-23, IL-21, IL-6 and IL-2, IL-2L respectively with TGF-ß1as a common precursor.