Cytolytic CD4 cells: Direct mediators in infectious disease and malignancy

Abstract

CD4 T cells have traditionally been regarded as helpers and regulators of adaptive immune responses; however, a novel role for CD4 T cells as direct mediators of protection against viral infections has emerged. CD4 T cells with cytolytic potential have been described for almost 40 years, but their role in host protection against infectious disease is only beginning to be realized. In this review, we describe the current literature identifying these cells in patients with various infections, mouse models of viral infection and our own work investigating the development of cytolytic CD4 cells in vivo and in vitro. CD4 CTL are no longer considered an artefact of cell culture and may play a physiological role in viral infections such as EBV, CMV, HIV and influenza. Therefore, vaccine strategies aimed at targeting CD4 CTL should be developed in conjunction with vaccines incorporating B cell and CD8 CTL epitopes.

Figure 1

A) Model of differentiation of human CD4 CTL. In many chronic infections induce a population of CD4 T cells with cytolytic capacity. These cells are found in peripheral blood and are believed to represent a terminally differentiated effector cell that is CD28^-, CD27⁺, GrB⁺, perforin⁺ and in some cases also expresses CD57. B) Differentiation of CD4 CTL in a mouse model of acute infection. In the draining lymph node, CD4 cells produce IL-2, are CD27⁺ and CD62L^+/-. As cells differentiate and migrate to the lung, they lose surface CD62L, acquire CD43 and begin to lose CD27. The ability to secrete IFN-γ and lyse target cells is also acquired as cells migrate to the lung.

Figure 2

Model of CD4 CTL differentiation in vitro. Naïve CD4 cells can be differentiated into various subsets based on the cytokines present early in the culture. Th0 effectors are those incubated in the presence of IL-2 and exhibit high levels of cytotoxicity. Th0 cells also secrete a combination of Th1 and Th2 type cytokines. Th1 effectors also demonstrate high levels of GrB expression and cytotoxicity while Th2 effectors are less able to lyse target cells and Th17 cells demonstrate little, if no cytolytic activity.