Interferon-gamma is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-gamma response by CD4(+) T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4(+) T cell population in the lung. The recall response of the IL-17-producing CD4(+) T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4(+) T cells producing interferon-gamma in the lung. We propose that vaccination induces IL-17-producing CD4(+) T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4(+) T cells producing interferon-gamma, which ultimately restrict bacterial growth.

Viral pathogens often generate strong CD4+ T cell responses that are best known for their ability to help B cell and CD8+ T cell responses. However, recent studies reveal additional roles for CD4+ T cells, some of which are independent of other lymphocytes, and indicate that memory cells are more effective in most functions than naïve CD4 T cells. Here, we review the full spectrum of antiviral functions of CD4+ T cells, including their helper activities, innate immune induction, and direct anti-viral roles, and suggest how these functions are integrated to provide highly protective responses against viral pathogens.

Although B cells produce cytokines it is not known whether B cells can differentiate into effector subsets that secrete polarized arrays of cytokines. We have identified two populations of "effector" B cells (Be1 and Be2) that produce distinct patterns of cytokines depending on the cytokine environment in which the cells were stimulated during their primary encounter with antigen and T cells. These effector B cell subsets subsequently regulate the differentiation of naïve CD4+ T cells to TH1 and TH2 cells through production of polarizing cytokines such as interleukin 4 and interferon gamma. In addition, Be1 and Be2 cells could be identified in animals that were infected with pathogens that preferentially induce a Type 1 and Type 2 immune response. Together these results suggest that, in addition to their well defined role in antibody production, B cells may regulate immune responses to infectious pathogens through their production of cytokines.

Immunological memory can be defined as the faster and stronger response of an animal that follows reexposure to the same antigen. By this definition, it is an operational property of the whole animal or the immune system. Memory cells express a different pattern of cell surface markers, and they respond in several ways that are functionally different from those of naive cells. Murine memory cells are CD44 high and low in the expression of activation markers such as CD25 (IL-2R), whereas human memory cells are CD45RA-, CD45RO+. In contrast to naive cells, memory cells secrete a full range of T cell cytokines and can be polarized to secrete particular restricted patterns of secretion for both CD4 and CD8 T cells. The requirements for the activation of memory cells for proliferation and cytokine production are not quite as strict as those of naive cells, but costimulation in the broad sense is required for optimum responses and for responses to suboptimum antigen concentrations. It would appear that memory cells can persist in the absence of antigenic stimulation and persist as nondividing cells. Reencounter with the same antigen can expand the population to a new, stable, higher level and generate a separate population of CD44 high effectors that may be required for protection, while competition from other antigens can drive it down to a lower stable level. It is unclear how or where memory cells arise, but once generated they have different pathways of recirculation and homing.

The immune response of naive CD4 T cells to influenza virus is initiated in the draining lymph nodes and spleen, and only after effectors are generated do antigen-specific cells migrate to the lung which is the site of infection. The effector cells generated in secondary organs appear as multiple subsets which are a heterogeneous continuum of cells in terms of number of cell divisions, phenotype and function. The effector cells that migrate to the lung constitute the more differentiated of the total responding population, characterized by many cell divisions, loss of CD62L, down-regulation of CCR7, stable expression of CD44 and CD49d, and transient expression of CCR5 and CD25. These cells also secrete high levels of interferon γ and reduced levels of interleukin 2 relative to those in the secondary lymphoid organs. The response declines rapidly in parallel with viral clearance, but a spectrum of resting cell subsets reflecting the pattern at the peak of response is retained, suggesting that heterogeneous effector populations may give rise to corresponding memory populations. These results reveal a complex response, not an all-or-none one, which results in multiple effector phenotypes and implies that effector cells and the memory cells derived from them can display a broad spectrum of functional potentials.

We show here that IL-17-secreting CD4 T (Th)17 and CD8 T (Tc)17 effector cells are found in the lung following primary challenge with influenza A and that blocking Ab to IL-17 increases weight loss and reduces survival. Tc17 effectors can be generated in vitro using naive CD8 T cells from OT-I TCR-transgenic mice. T cell numbers expand 20-fold and a majority secretes IL-17, but little IFN-γ. Many of the IL-17-secreting cells also secrete TNF and some secrete IL-2. Tc17 are negative for granzyme B, perforin message, and cytolytic activity, in contrast to Tc1 effectors. Tc17 populations express message for orphan nuclear receptor γt and FoxP3, but are negative for T-bet and GATA-3 transcription factors. The FoxP3-positive, IL-17-secreting and IFN-γ-secreting cells represent three separate populations. The IFN-γ-, granzyme B-, FoxP3-positive cells and cells positive for IL-22 come mainly from memory cells and decrease in number when generated from CD44low rather than unselected CD8 T cells. Cells of this unique subset of CD8 effector T cells expand greatly after transfer to naive recipients following challenge and can protect them against lethal influenza infection. Tc17 protection is accompanied by greater neutrophil influx into the lung than in Tc1-injected mice, and the protection afforded by Tc17 effectors is less perforin but more IFN-γ dependent, implying that different mechanisms are involved.

T helper cell (Th) 1, but not Th2, effectors undergo rapid Fas/Fas ligand (FasL)-mediated, activation-induced cell death upon restimulation with antigen. Unequal apoptosis is also observed without restimulation, after a longer lag period. Both effectors undergo delayed apoptosis induced by a non–Fas-mediated pathway. When Th1 and Th2 effectors are co-cultured, Th2 effectors survive preferentially, suggesting the responsible factor(s) is intrinsic to each population. Both Th1 and Th2 effectors express Fas and FasL, but only Th2 effectors express high levels of FAP-1, a Fas-associated phosphatase that may act to inhibit Fas signaling. The rapid death of Th1 effectors leading to selective Th2 survival provides a novel mechanism for differential regulation of the two subsets.

The factors required for the generation of memory CD4 T cells remain unclear, and whether there is a continuing requirement for antigen stimulation is critical to design of vaccine strategies. CD4 effectors generated in vitro from naïve CD4 T cells of mice efficiently gave rise to small resting memory cells after transfer to class II-deficient hosts, indicating no requirement for further antigen or class II recognition.