The article discusses the importance of T-cell quality in mediating protective immunity against various infections and the implications for vaccine design. T cells play a crucial role in protecting against infections, and the development of effective vaccines against HIV, malaria, and tuberculosis requires generating potent and durable T-cell responses. However, quantifying protective T-cell responses has been challenging due to the complexity and heterogeneity of T-cell functions. Multiparameter flow cytometry has emerged as a powerful tool to assess the functional capacity of T cells, allowing simultaneous measurement of multiple effector functions and phenotypes. The quality of T-cell responses, defined by the ability to produce multiple cytokines and perform various effector functions, is crucial for determining disease outcomes. Recent studies in mice, non-human primates, and humans have shown that the quality of T-cell responses, particularly the frequency of multifunctional T cells, correlates strongly with protection against infections. For example, in HIV infection, long-term non-progressors (LTNPs) exhibit higher frequencies of multifunctional CD4+ T cells compared to progressors, which are associated with better control of viral load and slower disease progression. The article also highlights the importance of considering both the magnitude and quality of T-cell responses in vaccine design. Different vaccine formulations, such as replication-defective adenovirus (rADV) vectors and recombinant poxvirus vectors, can elicit distinct T-cell responses in terms of both magnitude and quality. Prime-boost immunization strategies can further influence the quality of T-cell responses, with higher doses of rADV vaccines generally eliciting stronger but less multifunctional responses compared to lower doses. Overall, the article emphasizes the need for a comprehensive understanding of T-cell quality and its impact on protective immunity, suggesting that optimizing the quality of T-cell responses may be as important as increasing their magnitude for developing effective vaccines against infectious diseases.The article discusses the importance of T-cell quality in mediating protective immunity against various infections and the implications for vaccine design. T cells play a crucial role in protecting against infections, and the development of effective vaccines against HIV, malaria, and tuberculosis requires generating potent and durable T-cell responses. However, quantifying protective T-cell responses has been challenging due to the complexity and heterogeneity of T-cell functions. Multiparameter flow cytometry has emerged as a powerful tool to assess the functional capacity of T cells, allowing simultaneous measurement of multiple effector functions and phenotypes. The quality of T-cell responses, defined by the ability to produce multiple cytokines and perform various effector functions, is crucial for determining disease outcomes. Recent studies in mice, non-human primates, and humans have shown that the quality of T-cell responses, particularly the frequency of multifunctional T cells, correlates strongly with protection against infections. For example, in HIV infection, long-term non-progressors (LTNPs) exhibit higher frequencies of multifunctional CD4+ T cells compared to progressors, which are associated with better control of viral load and slower disease progression. The article also highlights the importance of considering both the magnitude and quality of T-cell responses in vaccine design. Different vaccine formulations, such as replication-defective adenovirus (rADV) vectors and recombinant poxvirus vectors, can elicit distinct T-cell responses in terms of both magnitude and quality. Prime-boost immunization strategies can further influence the quality of T-cell responses, with higher doses of rADV vaccines generally eliciting stronger but less multifunctional responses compared to lower doses. Overall, the article emphasizes the need for a comprehensive understanding of T-cell quality and its impact on protective immunity, suggesting that optimizing the quality of T-cell responses may be as important as increasing their magnitude for developing effective vaccines against infectious diseases.