A vital role of IL-21 in control of a chronic viral infection

Source: Yi JS, Du M, Zajac AJ. A vital role for interleukin-21 in the control of a

chronic viral infection. Science. 2009 Jun 19;324(5934):1572-6. Epub 2009 May 14.

PubMed PMID: 19443735; PubMed Central PMCID: PMC2736049.

 

CD4+ and CD8+ T cell responses play a major role in body's fight against viral infections. Earlier studies have shown that during the initial phases of many viral infections, CD8+ T cell responses are induced but they are failed to attain elaborate effector functions. The reason for this is not known. Although, it is known that in the absence of CD4+ T cell help, CD8+ T cell functions are impaired. CD4+ T cells are the primary producers of Interleukin-21 (IL-21). IL-21 has many functions; some of which are inducing the development of Th17 and follicular helper T cells (Tfh). As it has been shown that CD4+ help is essential for effective CD8+ cell response, the authors of this paper studied the role of IL-21 in CD8+ T cell responses to viral infections.

This paper is from the laboratory of Dr. Allan J Zajac, Department of microbiology, University of Alabama at Birmingham, US. In an earlier study, the authors observed a marked difference in the induction of IL-21+CD4+ T cells following acute LCMV Armstrong (arm) and chronic LCMV clone-13 (Cl-13) infections in C57BL/6 mice. They observed that although both groups of mice showed polyclonal virus specific CD4+IL21+ T cells by eight day of infection, this response was 7.8 times lower in mice infected with Cl-13.

This pronounced IL21+ CD4+ response in LCMV-Arm infected mice let the investigators to investigate whether IL-21 influences the generation of germinal center (GC) B cells, Tfh cells and antibody response. They observed that the percentage and number of GC B cells, Tfh T cells as well as LCMV-specific antibody titers were similar in IL21+/+ and IL21-/- mice, following 8-9 days of LCMV-arm infection. These results suggest that acute LCMV infection can trigger these responses even in the absence of IL21. Next, the authors analyzed responses of IL21-/-, Il21+/- and Il21+/+ mice to LCMV-Cl-13 infection. They observed that eight days after infection, the magnitude of anti-viral CD4+ and CD8+ T cell responses and the frequency of interferon gamma producing CD8+ T cells were similar among the three groups of mice. However, they observed differences in their functional quality. Both the percentages and absolute numbers of polyfunctional, IL-2 producing CD8+ T cells were reduced in IL21-/- and IL21-/+ mice. A similar trend for TNF-alpha production was observed. These results indicate that IL-21 deficiency results in impaired polyfunctional effector CD8+ T cell responses during initial phase of LCMV infection.

Furthermore, the authors checked the viral loads in these three groups of mice following LCMV-Cl-13 infection. They found that viral titers were highest in IL21-/- mice. These data suggest that IL-21 is critical for control of chronic viral infections. When the authors examined the anti-viral CD8+ T cell responses at later stages of LCMV-Cl13 infection, they found that by 136 day, infection was under control in IL21+/+ mice. IFN-gamma, IL-2 and TNF-alpha production was detectable by CD8+ T cells and these CD8+ T cells were CD43intermediate, programmed death -1 (PD-1) low. This phenotype is similar to resting memory T cells. In contrast, IL-2, IFN-gamma, and TNF-alpha production were highly reduced by CD8+ T cells in IL21-/- mice and these cells were CD43high, PD-1 high, a phenotype which is hallmark of exhaustion that develops in chronically infected hosts. These results clearly indicate that the absence of IL-21 production results in a failure to contain the infection and a substantial reduction in antiviral CD8+ T cell functions.

The next objective was to determine whether IL-21 acts directly to promote and sustain CD8+ T cell responses. Thus, the cohorts of IL21r+/+ / IL21r-/- (experimental) and IL21r+/+/IL21r+/+ (control) mixed bone-marrow chimeras were infected with LCMV-Cl-13 and CD8+ T cell responses were evaluated over time. The authors observed that both the IL21r+/+ and IL21r-/- CD8+ T cells were detectable in circulation following day 8 of infection. In contrast at 16^th day following infection, a preferential and rapid loss of IL21r-/- CD8+ T cells was observed. These data indicate that IL-21 is directly required for supporting and maintaining anti-viral CD8+ T cells during chronic viral infection.

To evaluate whether the addition of IL-21 enhanced anti-viral CD8+ T cells, the authors also performed experiments in which IL21 was administered to LCMV-Cl-13 infected CD4-/- mice. They found that daily injection of recombinant Il-21 to these mice, enhanced the functional quality of anti-viral CD8+ T cells.

Conclusions: The findings presented in this paper are quite interesting and throw new light into the role of IL-21 in successful control of infection. the authors showed that IL21 plays important role in induction of an effector CD8+ T cell response.

In authors words, " we anticipate that the cautious development of approaches to modulate the levels of IL-21, or regulate the induction of cellular subsets that generate IL-21, will provide new therapeutic opportunities to improve immunity to diseases that require CD8+ T cell responses to be controlled, such as chronic viral infection and tumors".