Dengue immune response: low affinity, high febrility

Immunity built up after dengue virus infection protects only poorly against reinfection by a virus of a different serotype, and second infections are often even more severe. A new study examines why (pages 921–927).

The immune response to viruses treads a fine line between damage to the host and control of the pathogen. In the face of this delicate balance, partial or incomplete immunity to a pathogen can sometimes be worse than no immunity. Nowhere in nature is this more apparent than in dengue virus infection. Dengue is a mosquito-borne tropical disease caused by any of four serotypes of the flavivirus of the same name. Immunity to a given dengue virus serotype provides good protection against reinfection by that same serotype. However, subsequent infection with other viral serotypes markedly increases the risk for dengue hemorrhagic fever (DHF) and dengue shock syndrome, the severe forms of dengue virus infection marked by abnormal vascular permeability1.

In this issue, Mongkolsapaya et al. report that a substantial fraction of T cells activated during the second infection have poor affinity for the antigenic peptides of this second virus serotype2. Instead, these T cells have higher affinity to other (presumably previously encountered) dengue virus serotypes. The authors suggest that these 'inappropriate' T cells contribute to immunopathology while doing little to clear the virus.

Dengue has not attracted widespread attention from researchers in the developed world, but it is a major public health concern in tropical areas. Worldwide, hundreds of thousands of people contract DHF every year, and often require hospitalization to prevent death; most of these cases occur during second dengue virus infections. The number of countries affected by dengue and the number of cases of DHF have increased over the last several decades3. There is an urgent need for vaccines against dengue virus, but the theoretical potential for a vaccine to induce a detrimental immune response, enhancing the risk for DHF, has been a serious impediment to its development.

These small flaviviruses encode only ten proteins, and the serotypes have high amino acid sequence homology. Dengue virus serotypes can be distinguished by antibody neutralization assays, but they elicit antibody and T-cell responses that cross-react against other serotypes. Classic studies by Halstead and others led to the hypothesis that infection with a second dengue virus serotype results in antibody-mediated immune enhancement4. In this process, non-neutralizing antibody to the first dengue serotype binds to the second serotype.

This binding enhances infection of phagocytic cells by the second serotype through an antibody (Fc) receptor entry route4. Antibody-mediated enhancement of infection also can explain the occurrence of DHF during primary dengue virus infection in infants; this is typically observed in the second 6 months of life, when dengue-specific antibodies acquired from the mother decline below protective (neutralizing) levels.

The pathogenesis of DHF cannot entirely be explained by antibody, however. DHF is associated with high levels of T-cell cytokines such as IFN-γ and TNF-α, and evidence of marked T-cell activation in addition to high viremia levels5. To study T-cell responses after second dengue virus infections, the investigators first identified a peptide epitope recognized in the context of HLA-A*1101, an allele common in the Thai population. As with previously described T-cell epitopes, the corresponding epitopes from the different dengue virus serotypes showed highly similar but not identical sequences, indicating a potential for partial cross-reactivity6.

In several patients, the authors found that the CD8+ T cells generated during infection bound weakly to major histocompatibility complex tetramers presenting epitopes of the infecting virus, but bound more strongly to other epitopes, presumably from previously encountered viruses. A high frequency of these T cells induced during the second infection displayed an apoptotic phenotype and seemed destined to die before adequately controlling the infection.

The authors interpreted this phenomenon as 'original antigenic sin' of T cells, whereby cross-reactive T cells to one pathogen dominate a response to a related pathogen7,8. Cross-reactive T cells expanded by the previously encountered dengue virus serotype may prevail over T cells with higher affinity for the new serotype because of their numerical advantage and memory phenotype (Fig. 1). This phenomenon of immunodomination may occur by T-cell competition for antigen on the antigen-presenting cells9, and is an important aspect of the heterologous T-cell immunity that can result from cross-reactive T-cell responses, even between relatively unrelated viruses10.

Figure 1: Low-affinity T-cell response to dengue antigens after secondary (sequential) infection.
figure1

M.A. Brehm

Circles represent the distribution of T-cell clones of different affinities to cross-reactive peptide epitopes. (a) Serotype-specific responses tend to select for higher affinity T cells during acute primary infections. (b) Upon infection with a second virus serotype, the response is dominated by T cells of higher affinity to the first encountered virus (in this example, dengue 2). This could be due to a preferential expansion of pre-existing low-affinity memory T cells. Alternatively, the higher affinity cells may be driven into activation-induced cell death (AICD) by the high antigen load caused by antibody-mediated enhancement of infection. Whatever the mechanism, the consequences may be inefficient viral clearance and enhanced immunopathology in the form of DHF. D2, dengue 2; D3, dengue 3.

An alternative explanation for these observations is that enhanced viral replication caused by antibody-mediated immune enhancement may drive the T cells with highest affinity for the infecting virus into apoptosis, through the process of activation-induced cell death11 (Fig. 1). Definitive evidence of one or both of these mechanisms is likely to come from prospective cohort studies. By either mechanism, the host is left with a weak and ineffective group of T cells to clear the infection.

If these detrimental T cells contribute to DHF pathogenesis, might their role involve mechanisms other than inefficient viral clearance? This seems likely, because animal models have shown that immunopathology occurs when T cells are of low affinity and continue to secrete cytokines in the presence of residual antigen12. Mouse models of heterologous immunity have similarly shown marked changes in pathology when T cells specific to previously encountered viruses alter the response to subsequent virus infections10.

Understanding the relationship between positive and negative effects of the T-cell response to dengue virus infections might permit the design of vaccines to minimize the induction of low avidity cross-reactive immune responses. The need for a safe and effective vaccine is certainly great, and it is to be hoped that the application of new immunologic techniques, such as those used by the authors, will provide the necessary clues.

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Welsh, R., Rothman, A. Dengue immune response: low affinity, high febrility. Nat Med 9, 820–822 (2003). https://doi.org/10.1038/nm0703-820

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