Multipronged CD4(+) T-cell effector and memory responses cooperate to provide potent immunity against respiratory virus - PubMed (original) (raw)

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Multipronged CD4(+) T-cell effector and memory responses cooperate to provide potent immunity against respiratory virus

Tara M Strutt et al. Immunol Rev. 2013 Sep.

Abstract

Over the last decade, the known spectrum of CD4(+) T-cell effector subsets has become much broader, and it has become clear that there are multiple dimensions by which subsets with a particular cytokine commitment can be further defined, including their stage of differentiation, their location, and, most importantly, their ability to carry out discrete functions. Here, we focus on our studies that highlight the synergy among discrete subsets, especially those defined by helper and cytotoxic function, in mediating viral protection, and on distinctions between CD4(+) T-cell effectors located in spleen, draining lymph node, and in tissue sites of infection. What emerges is a surprising multiplicity of CD4(+) T-cell functions that indicate a large arsenal of mechanisms by which CD4(+) T cells act to combat viruses.

Keywords: T-helper cells; cell differentiation; cytokines; cytotoxic T cells; infectious diseases; memory.

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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Figures

Figure 1

Figure 1. Defining CD4 T cell subsets

The state of activation, cytokine production profile, functional potential, and anatomical location can all be used to characterize and place CD4 T cells into distinct subsets.

Figure 2

Figure 2. Phases of memory CD4 T cell protective functions

Following challenge with a pathogen, memory CD4 T cells mediate protection at different times and in different organs. Early at sites of infection, memory CD4 T cells resident in tissues, or inflammatory inducing memory T cells (ThII), enhance innate inflammatory responses and activate antigen presenting cells and other innate cells to control pathogen levels. This is followed by memory CD4 T cell provision of help for antibody producing B cells and help for CD8 T cells in the secondary lymphoid organs (SLO). At the peak of the response, memory CD4 T cells that migrate to sites of infection and produce cytokines and chemokines and kill infected cells to control and clear the pathogen.

Figure 3

Figure 3. Th17 effector protection does not require IL-17 production

5×106 Th17-polarized effector CD4 T cells (OT-II transgenic) recognizing IAV were transferred to either WT or IL-17 receptor-deficient (IL-17R KO) hosts. All mice were challenged with a lethal (2 LD50) dose of IAV expressing OVAII peptide and survival and weight loss monitored. Th17 effector transfer rescued both WT and IL-17R KO host survival (left), but IL-17R KO mice lost less weight (right) (n=4-6 mice/group).

Figure 4

Figure 4. Secondary effectors derived from in vitro generated Th1 memory CD4 T cells show organ-specific differences in gene expression following IAV challenge

Heat map, generated using GeneSifter (GeoSpiza), showing the signal strength of genes differentially expressed by secondary CD4 T cell effectors isolated from the spleen, draining lymph node (dLN), and lung 7 days post IAV infection.

Figure 5

Figure 5. Compartmentalization of CD4 T cell effector functions during IAV challenge

Following activation of naive cells in the draining lymph node (dLN) by antigen presenting cells (APC) displaying viral antigen (Ag), activated effector cells develop that traffic to the spleen and lung. Functional analysis reveals that effectors present in secondary lymphoid organs (spleen and dLN) are strikingly different from the effector cells responding in the lung.

Figure 6

Figure 6. Compartmentalization of transcriptional regulators in CD4 T cell effectors following IAV challenge

Heat map, generated using Gene-E (Broad Institute), showing the signal strength of genes in the DAVID ontogeny pathway of transcriptional regulation differentially expressed by primary CD4 T cell effectors isolated from the spleen, draining lymph node (dLN), and lung at 7 days post infection.

Figure 7

Figure 7. Differential expression of Blimp-1 in CD4 T cell effectors following IAV challenge

Relative signal of the gene encoding Blimp-1, prdm1, in CD4 T cell effectors isolated from the secondary lymphoid organs (SLO) versus the lung at 7 days post infection.

Figure 8

Figure 8. CD4 T cell effector subset generation

Following initial activation Bcl-6 and Blimp-1 reciprocally regulate the generation of follicular Th (Tfh and GC-Tfh) vs. non-follicular (Nfh), which include the unique ThCTL subset.

Figure 9

Figure 9. Layers of CD4 T cell-mediated protection

Optimal protection against IAV provided by memory CD4 T cells requires memory CD4 T cells to synergize with B cells and CD8 T cells (either through synergies with the cells themselves, or alternatively, synergies of anti-viral memory CD4 T cell functions with the distinct anti-viral functions of B cells and CD8 T cells). Protection is similarly and substantially reduced if either B cells or CD8 T cells are absent, correlating with delayed viral clearance and enhanced disease. When memory CD4 T cells respond against the same dose of virus in mice lacking both CD8 T cells and B cells, protection and viral clearance are greatly compromised.

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