Plasticity of T cell memory responses to viruses

Abstract

Virus-specific memory T cell populations demonstrate plasticity in antigenic and functional phenotype, in recognition of antigen, and in their ability to accommodate new memory T cell populations. The adaptability of complex antigen-specific T cell repertoires allows the host to respond to a diverse array of pathogens and accommodate memory pools to many pathogens in a finite immune system. This is in part accounted for by crossreactive memory T cells, which can be employed in immune responses and mediate protective immunity or life-threatening immunopathology.

Figure 1

Plasticity of T Cell Repertoire during Viral Infections The colored dots represent T cell populations that have different specificities. The intracellular IFNγ staining for epitope-specific responses during particular viral infections are also depicted. A naive immune system is challenged with either of two heterologous viruses, LCMV or PV, and generates a T cell response to the immunodominant epitopes. These acute responses then decline but maintain the same hierarchy of immunodominant responses in the memory state. If an immune system that has been conditioned with one virus is exposed to the other heterologous virus, T cell populations that are crossreactive with the two viruses (red outlined) will expand preferentially, dominate the response, and go onto memory.

Figure 2

Private Specificity Drives Selective Expansion of Crossreactive Clones The colored dots represent unique T cell clones that all recognize the same antigen. In a naive host, each individual host develops a unique repertoire of antigen-specific cells to the same immunodominant epitope during LCMV infection. Depending on the private specificity of the TCR repertoire in each host, this repertoire may contain memory T cells crossreactive with allo-antigens (mouse A) or with autoantigens (mouse B). If there are LCMV-specific memory T cells crossreactive with a heterologous virus, such as VV, as in mouse A (yellow dots), these would preferentially expand upon infection with VV. A portion of the LCMV-specific memory T cells that are not crossreactive with the second virus VV (mouse B) are lost due to bystander attrition as the host accommodates the new memory T cells.

Figure 3

Previous Immunity to Influenza A Alters Early Cytokine Profiles and Immunopathology in the Lung on MCMV Infection During MCMV infection of influenza A-immune mice there is a dramatic alteration of early cytokine profiles in the lung, as measured by Rnase protection assay, with enhanced proinflammatory cytokines IL-6, IL-12, and IL-1, as well as IFNγ. Influenza A-immune mice have essentially normal lung architecture, with only mild residual scaring (ii). MCMV infection of naive mice results in mild mononuclear infiltrates (i), but MCMV infection in influenza A-immune mice results in a severe mononuclear pneumonia (iii) with evidence of bronchiolization (iv).

Figure 4

Accommodation of New Memory T Cells on Heterologous Virus Infection The colored dots represent T cell populations that have different specificities. The intracellular IFNγ staining for epitope-specific responses during particular viral infections are also depicted. The immunodominant hierarchy of antigen-specific responses is established during the peak of the CD8 T cell response to virus and remains the same during the silencing phase into memory for both LCMV and PV infection. After a heterologous virus infection, such as PV challenge of an LCMV-immune host, the LCMV-specific hierarchy is modified, the crossreactive-epitope responses (NP205) are preserved and expanded in response to PV infection, and the noncrossreactive epitope responses are reduced in number. In an LCMV-immune host, the PV-specific immunodominant hierarchy is different from that of a naive host, with the crossreactive epitope response (NP205) being immunodominant.