In 1966, at about the same time that Peyton Rouse and Charles Huggins shared the Nobel Prize in Medicine for their discoveries of tumor viruses and hormonal control of carcinoma, respectively, Claman, Chaperon, and Triplett published a seminal article in the The Journal of Immunology (1). The experimental data demonstrated that combinations of cells derived from adult thymus plus cells derived from bone marrow or adult spleen could act together after adoptive transfer to promote the production of hemolytic Abs. Irradiation destroyed the activity of the thymic cells, and a period of ∼1 wk was needed for maturation of both thymic cells and spleen cells, to realize the full synergistic effect. As stated in the summary, “the data confirmed the hypothesis of interaction between thymus and marrow cells, although the nature of this interaction is obscure” (1).

While immunologists today take for granted that T cells and B cells must interact to realize the full potential of the immune system to produce Ig, this was not always the case. In fact, for much of the early and mid portions of the 20th century, immunology was dominated by the view that Ab production and Ab-producing cells were the main, if not the only, function of the immune system (2). Immunology was dominated by intellectual and scientific approaches, which placed Ab production and Ab structure at the center of all considerations of the immune response. In the late 1950s and early 1960s there arose schools of thought termed “cis” and “trans” immunology. cis immunologists, or humoralists, believed that Ab binding of Ag was the central focus of the immune response, while trans immunologists, or cellularists, believed that the interaction of cells with Ag was the major focus of the immune system. Other debates that raged at this time or in earlier decades included whether Ehrlich’s Abs or Metchnikoff’s phagocytes were the main drivers of the immune response.

Within the context of what now seem to be quaint debates, some investigators pondered certain definitive experimental findings that did not fit with the current dogma and that could not be explained by a purely Ab-centric view of the immune system. Medawar had shown in the 1940s that transplantation graft rejection was unrelated to humoral Ab, despite many attempts to overturn this finding. The delayed-type hypersensitivity reaction had long been known to be unrelated to Ab, despite many attempts to negate these findings. In fact, elaborate theories were advanced that tried to explain DTH as a phenomenon related to cell-bound Ab (3). Lastly, while it was clear that the thymus was an important immunological organ, its precise function remained unknown and much conjecture centered on its function as an endocrine organ producing humoral mediators important for immune development and maturation.

The importance of the report by Claman et al. (1) is that it provides one of the very first and early demonstrations of the interaction between two different cell types. This almost heretical finding was called thymus and marrow synergism and later on, as new tools and approaches were developed, it would eventually be called T-B collaboration, or T cell help. Importantly, this report advanced the notion that two distinct cell types are needed to produce Ab, a concept well beyond the framework of cis and trans immunology. However, the nature of the critical intercellular events could not yet be more precisely defined since the distinction between T cells and B cells did not exist. Thy-1, the first T cell-specific marker, was described in the late 1960s; Lyt Ags were defined in the 1970s; mAbs were first produced in 1977; and the nosology of CD was not created until well into the 1980s. Thus, the tools needed to define Th cells and responder B cells did not exist in 1966.

Despite these technical limitations, it is worth noting that the techniques described in this paper, including irradiation, adoptive cell transfer, and immunization, are still in wide use today, and some were of recent provenance in 1966. Adoptive cell transfer techniques were developed in the 1940s and underwent continual refinements, as immunogenetics and histocompatibility became better understood. Immunofluorescence was first used in 1955, Jerne described the plaque assay in 1963 (reviewed in Ref.4), and culture techniques for lymphocytes underwent enormous advances in the 1950s and 1960s. Ab responses are now measured by ELISA or by fluorescent flow cytometry; techniques that are faster, easier, and more precise, particularly when compared with plaque assays or hemolysin titers. However, we must not forget that complement-dependent cytotoxicity is still very relevant, performed daily by virtually all clinical solid organ transplantation tissue typing labs to assure appropriate donor and recipient matching and avoid life threatening complications, such as hyperacute rejection. Likewise, the plaque assay is still the basis for current assays, such as ELISPOT, in which secretion of peptides by individual cells is enumerated. It is noteworthy that Claman et al. (1) pointed out that serum Ab did not strictly correlate with results in the plaque assay, anticipating later studies that demonstrated heterogeneous functions and distributions of B cell subtypes and Ig classes.

Within this report we may also discern the seeds of future myopic dogmas which placed the T cell at the very center of the immune system, to the exclusion of other cell types or other developmental pathways. Likewise, the ascendancy of the T cell-centric view of the immune universe in the late 1960s and early 1970s probably delayed the general recognition and acceptance that an entirely different class of cells, namely APCs, played novel and important roles in immunity.

The manuscript also teaches us about how scientific standards have changed. The manuscript is less than 4.5 pages, each 6 × 9 ¾ in; there are only 2 tables and 18 references. Further, there are no p values to assure us that the differences among groups are statistically significant. Lastly, it is noteworthy that there are some constants; the University of Colorado Medical Center in Denver has been, and remains, a formidable force in basic immunology.

1
Claman, H. N., E. A. Chaperon, R. F. Triplett.
1966
. Immunocompetence of transferred thymus-marrow cell combinations.
J. Immunol.
97
:
828
.
2
Silverstein, A. M..
2003
. Cellular versus humoral immunology: a century-long dispute.
Nat. Immunol.
4
:
425
.
3
Silverstein, A. M..
2002
. Whatever happened to cell-bound antibodies: on the overriding influence of dogma.
Nat. Immunol.
3
:
105
.
4
Silverstein, A. M..
2001
. The lymphocyte in immunology: from James B. Murphy to James L. Gowans.
Nat. Immunol.
2
:
569
.