Heterologous Immunity: Role in Natural and Vaccine-Induced Resistance to Infections

Abstract

The central paradigm of vaccination is to generate resistance to infection by a specific pathogen when the vacinee is re-exposed to that pathogen. This paradigm is based on two fundamental characteristics of the adaptive immune system, specificity and memory. These characteristics come from the clonal specificity of T and B cells and the long-term survival of previously-encountered memory cells which can rapidly and specifically expand upon re-exposure to the same specific antigen. However, there is an increasing awareness of the concept, as well as experimental documentation of, heterologous immunity and cross-reactivity of adaptive immune lymphocytes in protection from infection. This awareness is supported by a number of human epidemiological studies in vaccine recipients and/or individuals naturally-resistant to certain infections, as well as studies in mouse models of infections, and indeed theoretical considerations regarding the disproportional repertoire of available T and B cell clonotypes compared to antigenic epitopes found on pathogens. Heterologous immunity can broaden the protective outcomes of vaccinations, and natural resistance to infections. Besides exogenous microbes/pathogens and/or vaccines, endogenous microbiota can also impact the outcomes of an infection and/or vaccination through heterologous immunity. Moreover, utilization of viral and/or bacterial vaccine vectors, capable of inducing heterologous immunity may also influence the natural course of many infections/diseases. This review article will briefly discuss these implications and redress the central dogma of specificity in the immune system.

Keywords: T cells; antibody; heterologous (non-specific) effects of vaccines; heterologous immunity; innate and adaptive immune response.

Figure 1

Specificity vs. cross-reactivity of T cells. (A) According to the one-clone-one-specificity model, individual clones of T cells recognize one specific peptide epitope in the context of self MHC molecules, and do not recognize or get stimulated with any other peptide. (B) Model of T cell cross-reactivity implies an individual T cell clone can recognize multiple peptide epitopes in the context of the self MHC molecule.

Figure 2

Impact of specific vs. heterologous adaptive immunity on natural and vaccine-induced resistance to infection. (I) Depicts the results of specific immunity. Upon administration with vaccine against pathogen A, a limited repertoire of naïve T cells specific to antigens of vaccine A will be induced and an individual would be protected against subsequent exposure with pathogen A, but not against pathogens B and C. Similarly, exposure or infection with pathogen D will stimulate and expand T cells specific against D and protect against re-infection with pathogen D but not against subsequent infections with pathogens E and F. (II) Demonstrates the consequences of heterologous immunity. Upon administration with vaccine against A, a broad repertoire of cross-reactive T cells will be activated and expanded, and an individual would be protected against subsequent exposure with pathogen A, but also protected against pathogens B and C to some extent. Similarly, exposure or infection with pathogen D will induce cross-reactive T cells and protect against re-infection with pathogen D, but may also protect against subsequent infection with pathogens E and F. Therefore, the exposure history of an individual may modulate the outcome of future infections with multiple pathogens.