Several studies have used adoptive transfer of purified T cell subsets into immunodeficient mice to determine the subset of T cells responsible for mediating protection against Mycobacterium tuberculosis. These studies suggested that CD62L^hi memory CD4⁺ T cells from BCG-vaccinated mice are key for protection against tuberculosis. Importantly, we observed that transfer of naïve CD4⁺ T cells into Rag1−/− recipients protected against a mycobacterial challenge as well as transfer of BCG-experienced CD4⁺ T cells. We found that transfer of total CD4⁺ T cells from naïve mice or enriched CD62L^hiCD4⁺ T cells from BCG-vaccinated mice into Rag1−/− recipients induced severe colitis by 3 weeks post cell transfer, whereas transfer of CD62L^loCD4⁺ T cells from BCG-vaccinated mice did not. Naïve and CD62L^hiCD4⁺ T cells proliferated extensively upon transfer and developed an activated effector phenotype in the lung, even in the absence of infectious challenge. The induction of colitis and systemic cytokine response induced by the transfer and subsequent activation of CD4⁺ T cells from naïve mice or CD62L^hiCD4⁺ T cells from BCG-vaccinated mice, into immunodeficient recipients, may heighten their ability to protect against mycobacterial challenge. This raises doubts about the validity of this model to study CD4⁺ T cell-mediated protection against tuberculosis.